5-[3-[piperzin-1-yl]-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS 4 and 5 inhibitors for treating E.G. osteoarthritis

ABSTRACT

The present invention relates to compounds inhibiting ADAMTS, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of inflammatory diseases, and/or diseases involving degradation of cartilage and/or disruption of cartilage homeostasis by administering the compound of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the 35 U.S.C. 371 National Phase Application of PCTApplication No. PCT/EP2017/063272, filed Jun. 1, 2017, which claimspriority to GB Application No. 1610056.2, filed Jun. 9, 2016, thedisclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to hydantoin compounds, and their use inthe prophylaxis and/or treatment of inflammatory diseases, and/ordiseases involving degradation of cartilage and/or disruption ofcartilage homeostasis. In a particular aspect, the present compounds areADAMTS inhibitors, particularly ADAMTS-5 and/or ADAMTS-6. The presentinvention also provides methods for the production of a compound of theinvention, pharmaceutical compositions comprising a compound of theinvention, methods for the prophylaxis and/or treatment of inflammatorydiseases, and/or diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis by administering a compound of theinvention.

BACKGROUND OF THE INVENTION

Cartilage is an avascular tissue of which chondrocytes are the maincellular component. One of the functional roles of cartilage in thejoint is to allow bones to articulate on each other smoothly. Loss ofarticular cartilage, therefore, causes the bones to rub against eachother leading to pain and loss of mobility, and is the hallmark ofvarious diseases, among which rheumatoid arthritis and osteoarthritisare the most prominent.

The chondrocytes in normal articular cartilage occupy approximately 5%of the tissue volume, while the extra-cellular matrix makes up theremaining 95% of the tissue. The chondrocytes secrete the components ofthe matrix, mainly proteoglycans (including aggrecan) and collagens,which in turn supply the chondrocytes with an environment suitable fortheir survival under mechanical stress. Collagen type II, together withcollagen type IX, is arranged in solid fibril-like structures, andprovides cartilage with high mechanical strength properties, whereasaggrecan and other proteoglycans can absorb water and provide theresilient and shock-absorbing properties of the cartilage.

Under physiological conditions, cartilage homeostasis is maintained by abalance between the production (anabolism) and degradation (catabolism)of aggrecan and collagen. However, in OA and other joint disorders, thisbalance shifts toward catabolism. Loss of aggrecan occurs early in theonset of cartilage destruction, initially at the joint surface thenspreading more deeply at more advanced stages (Pond and Nuki, 1973).

Osteoarthritis (also referred to as OA, or wear-and-tear arthritis) isthe most common form of arthritis and is characterized by loss ofarticular cartilage, often associated with the subchondral bonere-modelling and pain. The disease mainly affects hands, spine andweight-bearing joints such as knees, and hips. During the diseaseprocess, the cartilage progressively deteriorates, which can be graded.At more advanced stages, the deeper layers of cartilage are affected,leading to calcification and exposure of the subchondral bone (Wielandet al., 2005).

The clinical manifestations of the development of the osteoarthritiscondition include: increased volume of the joint, pain, crepitation andfunctional disability that lead to pain and reduced mobility of thejoints. When disease further develops, pain at rest emerges. If thecondition persists without correction and/or therapy, the joint isdestroyed leading to disability.

Osteoarthritis is difficult to treat. At present, no cure is availableand treatment focuses on relieving pain and preventing the affectedjoint from becoming deformed. Common treatments are currently limited tosteroidal and non-steroidal anti-inflammatory drugs (NSAIDS), whichprovide symptomatic relief for pain and inflammation but do not arrestor slow down the progression of the disease (Mobasheri, 2013).

Therapeutic methods for the correction of the articular cartilagelesions that appear during the osteoarthritic disease have beendeveloped, but so far none of them have been able to slow down thedisease progression or to promote the regeneration of articularcartilage in situ and in vivo.

Although some dietary supplements as chondroitin and glucosamine sulfatehave been advocated as safe and effective options for the treatment ofosteoarthritis, a clinical trial revealed that both treatments did notreduce pain associated to osteoarthritis (Clegg et al., 2006).

In severe cases, joint replacement may be necessary. This is especiallytrue for hips and knees. If a joint is extremely painful and cannot bereplaced, it may be fused. This procedure stops the pain, but results inthe permanent loss of joint function, making walking and bendingdifficult.

Another possible treatment is the transplantation of cultured autologouschondrocytes. Here chondral cellular material is taken from the patient,sent to a laboratory where it is expanded. The material is thenimplanted in the damaged tissues to cover the tissue's defects.

Yet another treatment includes the intra-articular instillation of HylanG-F 20 (Synvisc, Hyalgan, Artz etc.), a substance that improvestemporarily the rheology of the synovial fluid, producing an almostimmediate sensation of free movement and a marked reduction of pain.

Other methods include application of tendinous, periosteal, facial,muscular or perichondral grafts; implantation of fibrin or culturedchondrocytes; implantation of synthetic matrices, such as collagen,carbon fiber; and administration of electromagnetic fields. All of thesehave reported minimal and incomplete effects, resulting in a poorquality tissue that can neither support the weighted load nor allow therestoration of an articular function with normal movement.

The ADAMTS family of secreted zinc metalloproteinases includes nineteenmembers that are known to bind and degrade extra cartilage matrix (ECM)components (Shiomi et al., 2010). Several members of the ADAMTS familyhave been found to cleave aggrecan, the major proteoglycan component ofcartilage: ADAMTS-1, -4, -5, -8, -9, -15, -16 and -18. Since theexpression and/or aggrecanase degrading activity of ADAMTS-1, -8, -9,-15, -16 and -18 are quite low, ADAMTS-4 (aggrecanase-1) and ADAMTS-5(aggrecanase-2) are believed to be the two major functional aggrecanases(Tortorella and Malfait, 2008).

Although the role of ADAMTS-6 remains unclear, it has been recentlyassociated with inguinal hernia (Jorgenson et al., 2015), vertebral discdegeneration diseases (Gruber et al., 2010), and Fabry disease (Shin etal., 2015).

ADAMTS-5 was identified in 1999 (Abbaszade et al., 1999). In 2005 twoindependent groups identified ADAMTS-5 as the principal aggrecanase inmouse cartilage (Glasson et al., 2005; Stanton et al., 2005).Proteolysis of aggrecan by ADAMTS-5 occurs at different sites: howevercleavage at the Glu373-Ala374 bond (aggrecan IGD) is likely moreimportant in the pathogenesis of osteoarthritis and inflammatoryarthritis since a loss of integrity at this bond results in the loss ofan entire aggrecan molecule, which is highly detrimental to cartilageintegrity and function (Little et al., 2007).

Studies in genetically engineered mouse models (GeMMs) have demonstratedthat ADAMTS-5 ablation protects against cartilage damage and aggrecanloss after osteoarthritis induction through surgical instability of themedial meniscus (DMM) (Glasson et al., 2005). Moreover in the DMM modelADAMTS-5 knock-out mice showed reduced subchondral bone changes (Batteret al., 2009) and did not develop osteoarthritis-associated mechanicalallodynia (Malfait et al., 2010). Besides preclinical evidence, clinicalevidence also indicates the importance of and interest in ADAMTS-5 as atarget for osteoarthritis. Recently, studies with an antibody targetingADAMTS-5 (Chiusaroli et al., 2013) have been reported. ELISA's have beendeveloped allowing the measurement of aggrecanase-derived cartilageneo-epitope levels in the synovial fluid as well as blood from rodentsto human. This method revealed increased levels of ADAMTS-5 derivedneo-epitope levels in the joints of rats in which cartilage degradationwas induced by meniscal tear as well as in joints of osteoarthritispatients, thereby providing further translational evidence for theimportance of this protease in the development of osteoarthritis(Chockalingam et al., 2011; Larsson et al., 2014).

These findings provide strong evidence for a central role of ADAMTS-5 inosteoarthritis pathology as a key target and an ADAMTS-5 inhibitorcapable to reach the joint cartilage at sufficient levels is expected toexert a protective effect on cartilage in osteoarthritic patients.

Matrix metalloproteinases (MMPs) constitute another family of 23 zincmetalloproteinases with many structural elements in common with ADAMTSfamily members (Georgiadis and Yiotakis, 2008). Clinical studies onbroad spectrum MMP inhibitors in oncology revealed that inhibition ofparticular MMPs was associated with poorer prognosis and undesirableside effects. In particular, MMP8 and MMP12 have been categorized asantitargets based on in vivo animal studies (Dufour and Overall, 2013).Therefore, there is a need for selective ADAMTS, and in particularADAMTS-5 inhibitors without affecting the activity of structurallyrelated MMPs, and more particularly MMP-8 and -12.

Therefore the identification of novel inhibitors of ADAMTS, inparticular ADAMTS-5, could provide desirable tools for the prophylaxisand/or treatment of diseases involving cartilage degradation, inparticular osteoarthritis, and/or rheumatoid arthritis.

It is therefore an object of the present invention to provide compoundsand their use in the prophylaxis and/or treatment of inflammatorydiseases, and/or diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis. In particular the compounds of thepresent invention are inhibitors of ADAMTS, and more particularlyADAMTS-5 and/or ADAMTS-6.

SUMMARY OF THE INVENTION

The present invention is based on the identification of novel hydantoincompounds that may be useful for the prophylaxis and/or treatment ofinflammatory diseases, and/or diseases involving degradation ofcartilage and/or disruption of cartilage homeostasis. In a particularaspect, the present compounds are ADAMTS inhibitors, particularlyADAMTS-5 and/or ADAMTS-6. The present invention also provides methodsfor the production of these compounds, pharmaceutical compositionscomprising these compounds and methods for treating inflammatorydiseases, and/or diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis by administering the compounds ofthe invention.

Accordingly, in a first aspect of the invention, the compounds of theinvention are provided having a Formula (I):

whereinR¹ is:

-   -   H,    -   C₁₋₄ alkyl optionally substituted with one or more independently        selected R⁴ groups,    -   C₃₋₇ monocyclic cycloalkyl optionally substituted with one or        more independently selected R⁴ groups,    -   4-7 membered monocyclic heterocycloalkyl comprising 1 to 2        heteroatoms independently selected from N, O, and S, optionally        substituted with one or more independently selected C₁₋₄ alkyl,        —C(═O)C₁₋₄ alkyl, or —C(═O)OC₁₋₄ alkyl,    -   phenyl optionally substituted with one or more independently        selected R⁵ groups,    -   phenyl fused to a 5-6 membered monocyclic heterocycloalkyl        comprising 1, 2 or 3 heteroatoms independently selected from N,        O, and S, which heterocycloalkyl is optionally substituted with        one or more ═O,    -   5-6 membered monocyclic heteroaryl comprising 1 or 2 heteroatoms        independently selected from

N, O, and S, optionally substituted with one or more independentlyselected R⁵ groups; R² is independently selected from:

-   -   H,    -   OH,    -   C₁₋₄ alkoxy, and    -   C₁₋₄ alkyl optionally substituted with one        -   OH,        -   —CN,        -   C₁₋₄ alkoxy optionally substituted with one phenyl, and        -   5-6 membered monocyclic heteroaryl comprising 1 or 2            heteroatoms independently selected from N, O, and S,            optionally substituted with one or more independently            selected C₁₋₄ alkyl;            each R^(3a), and R^(3b) is independently selected from H,            and C₁₋₄ alkyl optionally substituted with one or more halo;            Cy is    -   6-10 membered monocyclic or fused bicyclic aryl,    -   5-10 membered monocyclic or fused bicyclic heteroaryl comprising        1, 2 or 3 heteroatoms independently selected from N, O, and S;        R⁴ is    -   halo,    -   OH,    -   —CN,    -   C₁₋₄ alkyl,    -   C₁₋₄ alkoxy optionally substituted with one C₁₋₄ alkoxy, or        phenyl,    -   C₁₋₄ thioalkoxy,    -   4-7-membered monocyclic heterocycloalkyl comprising one or more        heteroatoms independently selected from N, S, and O, optionally        substituted with one or more halo, or —C(═O)OC₁₋₄ alkyl,    -   phenyl,    -   —S(═O)₂C₁₋₄ alkyl    -   —C(═O)OR^(7a)    -   —C(═O)NR^(7b)R^(7c)    -   —NHC(═O)OR^(7d)    -   —NHC(═O)R^(7e)    -   —NR^(8a)R^(8b);        each R⁵ is    -   halo,    -   OH,    -   —CN,    -   C₁₋₄ alkyl optionally substituted with one or more independently        selected halo, —NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d),    -   C₁₋₄ alkoxy optionally substituted with —NR^(9e)R^(9f), or    -   —S(═O)₂C₁₋₄ alkyl;        the subscript n is 0, 1, 2 or 3;        each R⁶ is independently selected from    -   halo,    -   —CN,    -   —NO₂,    -   —C₁₋₄ alkyl optionally substituted with one or more halo,    -   —C₁₋₄ alkoxy optionally substituted with one or more halo,    -   5-10 membered monocyclic or fused bicyclic heteroaryl comprising        1, 2 or 3 heteroatoms independently selected from N, O, and S,        optionally substituted with one or more independently selected        halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and    -   —NR^(9g)R^(9h);        each R^(7a), R^(7b), R^(7e), R^(7d), or R^(7e) is H, or C₁₋₄        alkyl optionally substituted with one OH or C₁₋₄ alkoxy;        each R^(8a), or R^(8b) is independently selected from H, and        C₁₋₄ alkyl optionally substituted with OH, C₁₋₄ alkoxy, or        phenyl;        each R^(9a), R^(9b), R^(9c), R^(9d), R^(9e), R^(9f), R^(9g), or        R^(9h) is independently selected from H, and C₁₋₄ alkyl;        or a pharmaceutically acceptable salt, or a solvate, or a        pharmaceutically acceptable salt of a solvate thereof; or a        biologically active metabolite thereof;        provided that the compound is not

-   5-[3-oxo-3-[4-(4-pyridinyl)-1-piperidinyl]propyl]-2,4-Imidazolidinedione    CAS#1422565-71-6,

-   5(S)-[3-oxo-3-[4-(1H-1,2,4-triazol-5-yl)-1-piperidinyl]propyl]-2,4-imidazolidinedione    CAS#1638335-41-7,

-   5(S)-[3-[4-(2-methoxyphenyl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1781306-72-6,

-   5-[3-[4-(5-methyl-4-pyrimidinyl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1638336-99-8,

-   5-[3-[4-(7-methyl-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1422561-83-8,

-   5-[3-[4-(6-fluoro-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1377848-53-7,

-   5-[3-[4-(3,5-dimethylimidazo[5,1-b]thiazol-7-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1287426-16-7, or

-   5-[3-[4-[4-methyl-5-(2-methyl-4-pyrimidinyl)-2-thiazolyl]-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1381179-03-8.

In a particular aspect, the compounds of the invention may exhibitselectivity towards the ADAMTS protease family, in particular towardsthe ADAMTS-5 and/or ADAMTS-6. In a further particular aspect, thecompounds of the invention may show low activity on MMP family members,in particular MMP8 and/or MMP12. Such selectivity may result in improveddrug safety and/or reduce off-target associated risks.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, and apharmaceutical carrier, excipient or diluent. In a particular aspect,the pharmaceutical composition may additionally comprise furthertherapeutically active ingredients suitable for use in combination withthe compounds of the invention. In a more particular aspect, the furthertherapeutically active ingredient is an agent for the prophylaxis and/ortreatment of inflammatory diseases, and/or diseases involvingdegradation of cartilage and/or disruption of cartilage homeostasis.

Moreover, the compounds of the invention, useful in the pharmaceuticalcompositions and treatment methods disclosed herein, arepharmaceutically acceptable as prepared and used.

In a further aspect of the invention, this invention provides a methodof treating a mammal, in particular humans, afflicted with a conditionselected from among those listed herein, and particularly inflammatorydiseases, and/or diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis, which method comprisesadministering an effective amount of the pharmaceutical composition orcompounds of the invention as described herein.

The present invention also provides pharmaceutical compositionscomprising a compound of the invention, and a suitable pharmaceuticalcarrier, excipient or diluent for use in medicine. In a particularaspect, the pharmaceutical composition is for use in the prophylaxisand/or treatment of inflammatory diseases, and/or diseases involvingdegradation of cartilage and/or disruption of cartilage homeostasis.

In a particular aspect, the compounds of the invention are provided foruse in the prophylaxis and/or treatment of osteoarthritis.

In additional aspects, this invention provides methods for synthesizingthe compounds of the invention, with representative synthetic protocolsand pathways disclosed later on herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

It will be appreciated that compounds of the invention may bemetabolized to yield biologically active metabolites.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

When describing the invention, which may include compounds,pharmaceutical compositions containing such compounds and methods ofusing such compounds and compositions, the following terms, if present,have the following meanings unless otherwise indicated. It should alsobe understood that when described herein any of the moieties definedforth below may be substituted with a variety of substituents, and thatthe respective definitions are intended to include such substitutedmoieties within their scope as set out below. Unless otherwise stated,the term “substituted” is to be defined as set out below. It should befurther understood that the terms “groups” and “radicals” can beconsidered interchangeable when used herein.

The articles ‘a’ and ‘an’ may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example ‘an analogue’ means one analogue or more than oneanalogue.

‘Alkyl’ means straight or branched aliphatic hydrocarbon having thespecified number of carbon atoms. Particular alkyl groups have 1 to 6carbon atoms or 1 to 4 carbon atoms. Branched means that one or morealkyl groups such as methyl, ethyl or propyl is attached to a linearalkyl chain. Particular alkyl groups are methyl (—CH₃), ethyl(—CH₂—CH₃), n-propyl (—CH₂—CH₂—CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂—CH₂—CH₂—CH₃), tert-butyl (—CH₂—C(CH₃)₃), sec-butyl(—CH₂—CH(CH₃)₂), n-pentyl (—CH₂—CH₂—CH₂—CH₂—CH₃), n-hexyl(—CH₂—CH₂—CH₂—CH₂—CH₂—CH₃), and 1,2-dimethylbutyl(—CHCH₃)—C(CH₃)H₂—CH₂—CH₃). Particular alkyl groups have between 1 and 4carbon atoms.

‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbongroups with the number of carbon atoms specified. Particular alkenyl has2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms,which can be straight-chained or branched and having at least 1 andparticularly from 1 to 2 sites of olefinic unsaturation. Particularalkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂),isopropenyl (—C(CH₃)═CH₂) and the like.

‘Alkylene’ refers to divalent alkene radical groups having the number ofcarbon atoms specified, in particular having 1 to 6 carbon atoms andmore particularly 1 to 4 carbon atoms which can be straight-chained orbranched. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂—CH₂—), or —CH(CH₃)— and the like.

‘Alkynylene’ refers to divalent alkyne radical groups having the numberof carbon atoms and the number of triple bonds specified, in particular2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas —C≡C—, —CH₂—C≡C—, and —C(CH₃)H—C≡CH—.

‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has thenumber of carbon atoms specified. In particular the term refers to thegroup —O—C₁₋₆ alkyl. Particular alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are loweralkoxy, i.e. with between 1 and 6 carbon atoms. Further particularalkoxy groups have between 1 and 4 carbon atoms.

‘Amino’ refers to the radical —NH₂.

‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. In particular aryl refers to an aromatic ringstructure, monocyclic or fused polycyclic, with the number of ring atomsspecified. Specifically, the term includes groups that include from 6 to10 ring members. Particular aryl groups include phenyl, and naphthyl.

‘Cycloalkyl’ refers to a non-aromatic hydrocarbyl ring structure,monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, withthe number of ring atoms specified. A cycloalkyl may have from 3 to 12carbon atoms, in particular from 3 to 10, and more particularly from 3to 7 carbon atoms. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

‘Cyano’ refers to the radical —CN.

‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) andiodo (I). Particular halo groups are either fluoro or chloro.

‘Hetero’ when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g.heteroaryl, and the like having from 1 to 4, and particularly from 1 to3 heteroatoms, more typically 1 or 2 heteroatoms, for example a singleheteroatom.

‘Heteroaryl’ means an aromatic ring structure, monocyclic or fusedpolycyclic, that includes one or more heteroatoms independently selectedfrom O, N and S and the number of ring atoms specified. In particular,the aromatic ring structure may have from 5 to 9 ring members. Theheteroaryl group can be, for example, a five membered or six memberedmonocyclic ring or a fused bicyclic structure formed from fused five andsix membered rings or two fused six membered rings or, by way of afurther example, two fused five membered rings. Each ring may contain upto four heteroatoms typically selected from nitrogen, sulphur andoxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms,more typically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered monocyclic heteroaryl groups include but arenot limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl,oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered monocyclic heteroaryl groups include but arenot limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl andtriazinyl.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five-membered ring include but are notlimited to imidazothiazolyl and imidazoimidazolyl.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl,isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g.adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl,and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl, and pteridinyl groups. Particularheteroaryl groups are those derived from thiophenyl, pyrrolyl,benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl,imidazolyl, oxazolyl and pyrazinyl.

Examples of representative heteroaryls include the following:

wherein each Y is selected from >C═O, NH, O and S.

‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure,monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, thatincludes one or more heteroatoms independently selected from O, N and Sand the number of ring atoms specified. The heterocycloalkyl ringstructure may have from 4 to 12 ring members, in particular from 4 to 10ring members and more particularly from 4 to 7 ring members. Each ringmay contain up to four heteroatoms typically selected from nitrogen,sulphur and oxygen. Typically the heterocycloalkyl ring will contain upto 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to2, for example a single heteroatom. Examples of heterocyclic ringsinclude, but are not limited to azetidinyl, oxetanyl, thietanyl,pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl),tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl,2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl),tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl(e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl,or piperazinyl.

As used herein, the term ‘heterocycloalkenyl’ means a‘heterocycloalkyl’, which comprises at least one double bond. Particularexamples of heterocycloalkenyl groups are shown in the followingillustrative examples:

wherein each W is selected from CH₂, NH, O and S; each Y is selectedfrom NH, O, C(═O), SO₂, and S; and each Z is selected from N or CH.

Particular examples of monocyclic rings are shown in the followingillustrative examples:

wherein each W and Y is independently selected from —CH₂—, —NH—, —O— and—S—.

Particular examples of fused bicyclic rings are shown in the followingillustrative examples:

wherein each W and Y is independently selected from —CH₂—, —NH—, —O— and—S—.

Particular examples of bridged bicyclic rings are shown in the followingillustrative examples:

wherein each W and Y is independently selected from —CH₂—, —NH—, —O— and—S— and each Z is selected from N and CH.

Particular examples of spirocyclic rings are shown in the followingillustrative examples:

wherein each Y is selected from —CH₂—, —NH—, —O— and —S—.

‘Hydroxyl’ refers to the radical —OH.

‘Oxo’ refers to the radical ═O.

‘Substituted’ refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).

‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as —SO₃H.

‘Thiol’ refers to the group —SH.

As used herein, term ‘substituted with one or more’ refers to one tofour substituents. In one embodiment it refers to one to threesubstituents. In further embodiments it refers to one or twosubstituents. In a yet further embodiment it refers to one substituent.

‘Thioalkoxy’ refers to the group —S-alkyl where the alkyl group has thenumber of carbon atoms specified. In particular the term refers to thegroup —S—C₁₋₆ alkyl. Particular thioalkoxy groups are thiomethoxy,thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy,tert-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lowerthioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particularalkoxy groups have between 1 and 4 carbon atoms.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non-aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

‘Pharmaceutically acceptable’ means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

‘Pharmaceutically acceptable salt’ refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g. an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term‘pharmaceutically acceptable cation’ refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like.

‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

‘Prodrugs’ refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

‘Solvate’ refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. This physical associationincludes hydrogen bonding. Conventional solvents include water, EtOH,acetic acid and the like. The compounds of the invention may be preparede.g. in crystalline form and may be solvated or hydrated. Suitablesolvates include pharmaceutically acceptable solvates, such as hydrates,and further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. ‘Solvate’ encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’are used interchangeably herein.

‘Effective amount’ means the amount of a compound of the invention that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “effective amount” can varydepending on the compound, the disease and its severity, and the age,weight, etc., of the subject to be treated.

‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiringor developing a disease or disorder (i.e. causing at least one of theclinical symptoms of the disease not to develop in a subject that may beexposed to a disease-causing agent, or predisposed to the disease inadvance of disease onset.

The term ‘prophylaxis’ is related to ‘prevention’, and refers to ameasure or procedure the purpose of which is to prevent, rather than totreat or cure a disease. Non-limiting examples of prophylactic measuresmay include the administration of vaccines; the administration of lowmolecular weight heparin to hospital patients at risk for thrombosisdue, for example, to immobilization; and the administration of ananti-malarial agent such as chloroquine, in advance of a visit to ageographical region where malaria is endemic or the risk of contractingmalaria is high.

‘Treating’ or ‘treatment’ of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e. arresting thedisease or reducing the manifestation, extent or severity of at leastone of the clinical symptoms thereof). In another embodiment ‘treating’or ‘treatment’ refers to ameliorating at least one physical parameter,which may not be discernible by the subject. In yet another embodiment,‘treating’ or ‘treatment’ refers to modulating the disease or disorder,either physically, (e.g. stabilization of a discernible symptom),physiologically, (e.g. stabilization of a physical parameter), or both.In a further embodiment, “treating” or “treatment” relates to slowingthe progression of the disease.

As used herein the term ‘inflammatory diseases’ refers to the group ofconditions including rheumatoid arthritis, osteoarthritis, juvenileidiopathic arthritis, psoriasis, psoriatic arthritis, allergic airwaydisease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease(COPD), inflammatory bowel diseases (e.g. Crohn's disease, ulcerativecolitis), endotoxin-driven disease states (e.g. complications afterbypass surgery or chronic endotoxin states contributing to e.g. chroniccardiac failure), and related diseases involving cartilage, such as thatof the joints. Particularly the term refers to rheumatoid arthritis,osteoarthritis, allergic airway disease (e.g. asthma), chronicobstructive pulmonary disease (COPD) and inflammatory bowel diseases.More particularly the term refers to rheumatoid arthritis, andosteoarthritis (OA). Most particularly the term refers to osteoarthritis(OA).

As used herein the term ‘allergic disease(s)’ refers to the group ofconditions characterized by a hypersensitivity disorder of the immunesystem including, allergic airway disease (e.g. asthma, rhinitis),sinusitis, eczema and hives, as well as food allergies or allergies toinsect venom.

As used herein the term ‘asthma’ as used herein refers to any disorderof the lungs characterized by variations in pulmonary gas flowassociated with airway constriction of whatever cause (intrinsic,extrinsic, or both; allergic or non-allergic). The term asthma may beused with one or more adjectives to indicate the cause.

As used herein the term ‘diseases involving degradation of cartilageand/or disruption of cartilage homeostasis’ includes conditions such asosteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis,gouty arthritis, septic or infectious arthritis, reactive arthritis,reflex sympathetic dystrophy, algodystrophy, achondroplasia, Paget'sdisease, Tietze syndrome or costal chondritis, fibromyalgia,osteochondritis, neurogenic or neuropathic arthritis, arthropathy,sarcoidosis, amylosis, hydarthrosis, periodical disease, rheumatoidspondylitis, endemic forms of arthritis like osteoarthritis deformansendemica, Mseleni disease and Handigodu disease; degeneration resultingfrom fibromyalgia, systemic lupus erythematosus, scleroderma andankylosing spondylitis. More particularly, the term refers toosteoarthritis (OA).

‘Compound(s) of the invention’, and equivalent expressions, are meant toembrace compounds of the Formula (e) as herein described, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g. hydrates, and the solvates of the pharmaceuticallyacceptable salts where the context so permits. Similarly, reference tointermediates, whether or not they themselves are claimed, is meant toembrace their salts, and solvates, where the context so permits.

When ranges are referred to herein, for example but without limitation,C₁₋₈ alkyl, the citation of a range should be considered arepresentation of each member of said range.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (Bundgard, H, 1985). Prodrugsinclude acid derivatives well known to practitioners of the art, suchas, for example, esters prepared by reaction of the parent acid with asuitable alcohol, or amides prepared by reaction of the parent acidcompound with a substituted or unsubstituted amine, or acid anhydrides,or mixed anhydrides. Simple aliphatic or aromatic esters, amides andanhydrides derived from acidic groups pendant on the compounds of thisinvention are particularly useful prodrugs. In some cases it isdesirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs arethe C₁₋₈ alkyl, C₂₋₈ alkenyl, C₆₋₁₀ optionally substituted aryl, and(C₆₋₁₀ aryl)-(C₁₋₄ alkyl) esters of the compounds of the invention.

As used herein, the term ‘isotopic variant’ refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an ‘isotopic variant’ of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitro (¹⁵N), or the like.It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³ N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed ‘isomers’. Isomersthat differ in the arrangement of their atoms in space are termed‘stereoisomers’.

Stereoisomers that are not mirror images of one another are termed‘diastereomers’ and those that are non-superimposable mirror images ofeach other are termed ‘enantiomers’. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e. as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a ‘racemic mixture’.

‘Tautomers’ refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of the invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

It will be appreciated that compounds of the invention may bemetabolized to yield biologically active metabolites.

The Invention

The present invention is based on the identification of novel hydantoincompounds that may be useful for the prophylaxis and/or treatment ofinflammatory diseases, and/or diseases involving degradation ofcartilage and/or disruption of cartilage homeostasis. In a particularaspect, the present compounds are ADAMTS inhibitors, particularlyADAMTS-5 and/or ADAMTS-6.

The present invention also provides methods for the production of thesecompounds, pharmaceutical compositions comprising these compounds andmethods for treating inflammatory diseases, and/or diseases involvingdegradation of cartilage and/or disruption of cartilage homeostasis byadministering the compounds of the invention.

Accordingly, in a first aspect of the invention, the compounds of theinvention are provided having a Formula (I):

whereinR¹ is:

-   -   H,    -   C₁₋₄ alkyl optionally substituted with one or more independently        selected R⁴ groups,    -   C₃₋₇ monocyclic cycloalkyl optionally substituted with one or        more independently selected R⁴ groups,    -   4-7 membered monocyclic heterocycloalkyl comprising 1 to 2        heteroatoms independently selected from N, O, and S, optionally        substituted with one or more independently selected C₁₋₄ alkyl,        —C(═O)C₁₋₄ alkyl, or —C(═O)OC₁₋₄ alkyl,    -   phenyl optionally substituted with one or more independently        selected R⁵ groups,    -   phenyl fused to a 5-6 membered monocyclic heterocycloalkyl        comprising 1, 2 or 3 heteroatoms independently selected from N,        O, and S, which heterocycloalkyl is optionally substituted with        one or more ═O,    -   5-6 membered monocyclic heteroaryl comprising 1 or 2 heteroatoms        independently selected from

N, O, and S, optionally substituted with one or more independentlyselected R⁵ groups; R² is independently selected from:

-   -   H,    -   OH,    -   C₁₋₄ alkoxy, and    -   C₁₋₄ alkyl optionally substituted with one        -   OH,        -   —CN,        -   C₁₋₄ alkoxy optionally substituted with one phenyl, and        -   5-6 membered monocyclic heteroaryl comprising 1 or 2            heteroatoms independently selected from N, O, and S,            optionally substituted with one or more independently            selected C₁₋₄ alkyl;            each R^(3a), and R^(3b) is independently selected from H,            and C₁₋₄ alkyl optionally substituted with one or more halo;            Cy is    -   6-10 membered monocyclic or fused bicyclic aryl,    -   5-10 membered monocyclic or fused bicyclic heteroaryl comprising        1, 2 or 3 heteroatoms independently selected from N, O, and S;        R⁴ is    -   halo,    -   OH,    -   —CN,    -   C₁₋₄ alkyl,    -   C₁₋₄ alkoxy optionally substituted with one C₁₋₄ alkoxy, or        phenyl,    -   C₁₋₄ thioalkoxy,    -   4-7-membered monocyclic heterocycloalkyl comprising one or more        heteroatoms independently selected from N, S, and O, optionally        substituted with one or more halo, or —C(═O)OC₁₋₄ alkyl,    -   phenyl,    -   —S(═O)₂C₁₋₄ alkyl    -   —C(═O)OR^(7a)    -   —C(═O)NR^(7b)R^(7c)    -   —NHC(═O)OR^(7d)    -   —NHC(═O)R^(7e)    -   —NR^(8a)R^(8b);        each R⁵ is    -   halo,    -   OH,    -   —CN,    -   C₁₋₄ alkyl optionally substituted with one or more independently        selected halo, —NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d),    -   C₁₋₄ alkoxy optionally substituted with —NR^(9e)R^(9f), or    -   —S(═O)₂C₁₋₄ alkyl;        the subscript n is 0, 1, 2 or 3;        each R⁶ is independently selected from    -   halo,    -   —CN,    -   —NO₂,    -   —C₁₋₄ alkyl optionally substituted with one or more halo,    -   —C₁₋₄ alkoxy optionally substituted with one or more halo,    -   5-10 membered monocyclic or fused bicyclic heteroaryl comprising        1, 2 or 3 heteroatoms independently selected from N, O, and S,        optionally substituted with one or more independently selected        halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and    -   —NR^(9g)R^(9h);        each R^(7a), R^(7b), R^(7c), R^(7d), or R^(7e), is H, or C₁₋₄        alkyl optionally substituted with one OH or C₁₋₄ alkoxy;        each R^(8a), or R^(8b) is independently selected from H, and        C₁₋₄ alkyl optionally substituted with OH, C₁₋₄ alkoxy, or        phenyl;        each R^(9a), R^(9b), R^(9c), R^(9d), R^(9e), R^(9f), R^(9g), and        R^(9h) is independently selected from H, and C₁₋₄ alkyl;        or a pharmaceutically acceptable salt, or a solvate, or a        pharmaceutically acceptable salt of a solvate thereof; or a        biologically active metabolite thereof;        provided that the compound is not

-   5-[3-oxo-3-[4-(4-pyridinyl)-1-piperidinyl]propyl]-2,4-Imidazolidinedione    CAS#1422565-71-6,

-   5(S)-[3-oxo-3-[4-(1H-1,2,4-triazol-5-yl)-1-piperidinyl]propyl]-2,4-imidazolidinedione    CAS#1638335-41-7,

-   5(S)-[3-[4-(2-methoxyphenyl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1781306-72-6,

-   5-[3-[4-(5-methyl-4-pyrimidinyl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1638336-99-8,

-   5-[3-[4-(7-methyl-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1422561-83-8,

-   5-[3-[4-(6-fluoro-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1377848-53-7,

-   5-[3-[4-(3,5-dimethylimidazo[5,1-b]thiazol-7-yl)-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1287426-16-7, or

-   5-[3-[4-[4-methyl-5-(2-methyl-4-pyrimidinyl)-2-thiazolyl]-1-piperidinyl]-3-oxopropyl]-2,4-Imidazolidinedione    CAS#1381179-03-8.

In one embodiment, a compound of the invention is according to FormulaII:

wherein R¹, R², R^(3a), R^(3b), R⁶, the subscript n and Cy are asdefined above.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R¹ is H.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is C₁₋₄ alkyl. In a particular embodiment,R¹ is Me, Et, Pr, iPr, or tBu. In a more particular embodiment, R¹ isMe, or Et. In a most particular embodiment, R¹ is Me

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is C₁₋₄ alkyl substituted with one or moreindependently selected R⁴ groups. In another embodiment, R¹ is Me, orEt, each of which is substituted with one or more independently selectedR⁴ groups. In a particular embodiment, R¹ is C₁₋₄ alkyl substituted withone, two or three independently selected R⁴ groups. In anotherparticular embodiment, R¹ is Me, or Et, each of which is substitutedwith one, two or three independently selected R⁴ groups. In a moreparticular embodiment, R¹ is C₁₋₄ alkyl substituted with one R⁴ group.In another more particular embodiment, R¹ is Me, or Et, each of which issubstituted with one R⁴ group. In a most particular embodiment, R¹ is—CH₂—R⁴.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R¹ is C₃₋₇ monocyclic cycloalkyl. In a particularembodiment, R¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In a more particular embodiment, R¹ is cyclopropyl.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is C₃₋₇ monocyclic cycloalkyl substitutedwith one or more independently selected R⁴ groups. In anotherembodiment, R¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each of which is substituted with one or more independently selected R⁴groups. In a particular embodiment, R¹ is C₃₋₇ monocyclic cycloalkylsubstituted with one, two or three independently selected R⁴ groups. Inanother particular embodiment, R¹ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each of which is substituted with one, twoor three independently selected R⁴ groups. In a more particularembodiment, R¹ is C₃₋₇ monocyclic cycloalkyl substituted with one R⁴group. In another more particular embodiment, R¹ is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substitutedwith one R⁴ group.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is halo, OH, and CN. In a more particular embodiment,each R⁴ is independently selected from F, Cl, OH, and CN.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is C₁₋₄ alkyl. In a particular embodiment, R⁴ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂. In a more particular embodiment, R⁴ is —CH₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is C₁₋₄ alkoxy. In a particular embodiment, R⁴ is OMe,OEt, or OiPr. In a more particular embodiment, R⁴ is OMe.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is C₁₋₄ alkoxy substituted with one C₁₋₄ alkoxy, orphenyl. In a particular embodiment, R⁴ is OMe, OEt, or OiPr, each ofwhich is substituted with one C₁₋₄ alkoxy, or phenyl. In a moreparticular embodiment, R⁴ is C₁₋₄ alkoxy substituted with one OMe, OEt,or phenyl. In another more particular embodiment, R⁴ is OMe, OEt, orOiPr, each of which is substituted with one OMe, OEt, or phenyl. In amost particular embodiment, R⁴ is —OCH₂—CH₂—OCH₃, —OCH₂-Ph.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is C₁₋₄ thioalkoxy. In a particular embodiment, R⁴ is—SCH₃, or —SCH₂CH₃. In a more particular embodiment, R⁴ is —SCH₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is 4-7-membered monocyclic heterocycloalkyl comprisingone or more heteroatoms independently selected from N, S, and O. In aparticular embodiment, R⁴ is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, ordioxanyl. In a more particular embodiment, R⁴ is azetidinyl,pyrrolidinyl, piperidinyl, or morpholinyl.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is 4-7-membered monocyclic heterocycloalkyl comprisingone or more heteroatoms independently selected from N, S, and O,substituted with one or more halo, —C(═O)OC₁₋₄ alkyl. In a particularembodiment, R⁴ is 4-7-membered monocyclic heterocycloalkyl comprisingone or more heteroatoms independently selected from N, S, and O,substituted with one, two or three independently selected F, Cl,—C(═O)OCH₃, —C(═O)OCH₂CH₃, or —C(═O)OC(CH₃)₃. In another particularembodiment, R⁴ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each ofwhich is substituted with one, two or three independently selected F,Cl, —C(═O)OCH₃, —C(═O)OCH₂CH₃, or —C(═O)OC(CH₃)₃. In a more particularembodiment, R⁴ is 4-7-membered monocyclic heterocycloalkyl comprisingone or more heteroatoms independently selected from N, S, and O,substituted with one F, Cl, —C(═O)OCH₃, —C(═O)OCH₂CH₃, or—C(═O)OC(CH₃)₃. In another particular embodiment, R⁴ is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl, each of which is substituted with one F,Cl, —C(═O)OCH₃, —C(═O)OCH₂CH₃, or —C(═O)OC(CH₃)₃. In a most particularembodiment, R⁴ is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl,each of which is substituted with one, two or three independentlyselected F, Cl. In another most particular embodiment, R⁴ is azetidinyl,pyrrolidinyl, piperidinyl, or morpholinyl, each of which is substitutedwith one —C(═O)OCH₃, —C(═O)OCH₂CH₃, or —C(═O)OC(CH₃)₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is phenyl.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —S(═O)₂C₁₋₄ alkyl. In a particular embodiment, R⁴is —S(═O)₂CH₃, or —S(═O)₂CH₂CH₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —C(═O)OR^(7a), and R^(7a) is as previouslydescribed. In a particular embodiment, R^(7a) is H. In anotherparticular embodiment, R^(7a) is C₁₋₄ alkyl. In yet another particularembodiment, R^(7a) is C₁₋₄ alkyl substituted with one OH, C₁₋₄ alkoxy.In a more particular embodiment, R^(7a) is Me, Et, iPr or tBu. Inanother more particular embodiment, R^(7a) is Me, Et, iPr or tBu, eachof which is substituted with one OH, C₁₋₄ alkoxy. In yet another moreparticular embodiment, R^(7a) is Me, Et, iPr or tBu, each of which issubstituted with one OH, —OCH₃. In a most particular embodiment, R⁴ is—C(═O)OCH₃, —C(═O)OCH₂CH₃, or —C(═O)OC(CH₃)₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —C(═O)NR^(7b)R^(7c), and each R^(7n) or R^(7c) isas previously described. In a particular embodiment, R^(7b) and R^(7c)are H. In another particular embodiment, one of R^(7b) or R^(7c) is H,and the other is C₁₋₄ alkyl. In yet another particular embodiment, oneof R^(7b) or R^(7c) is H, and the other is C₁₋₄ alkyl substituted withone OH, C₁₋₄ alkoxy. In a further particular embodiment, R^(7b) andR^(7c) are C₁₋₄ alkyl. In a more particular embodiment, one of R^(7b) orR^(7c) is H, and the other is Me, Et, iPr or tBu. In another moreparticular embodiment, one of R^(7b) or R^(7c) is H, and the other isMe, Et, iPr or tBu, each of which is substituted with one OH, C₁₋₄alkoxy. In yet another more particular embodiment, one of R^(7b) orR^(7c) is H, and the other is Me, Et, iPr or tBu, each of which issubstituted with one OH, —OCH₃. In a most particular embodiment, R⁴ is—C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, —C(═O)NHCH₂CH₂—OH or—C(═O)NHCH₂CH₂—OCH₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —NHC(═O)OR^(7d), and R^(7d) is as previouslydescribed. In a particular embodiment, R^(7d) is H. In anotherparticular embodiment, R^(7d) is C₁₋₄ alkyl. In yet another particularembodiment, R^(7d) is C₁₋₄ alkyl substituted with one OH, C₁₋₄ alkoxy.In a more particular embodiment, R^(7d) is Me, Et, iPr or tBu. Inanother more particular embodiment, R^(7d) is Me, Et, iPr or tBu, eachof which is substituted with one OH, C₁₋₄ alkoxy. In yet another moreparticular embodiment, R^(7d) is Me, Et, iPr or tBu, each of which issubstituted with one OH, —OCH₃. In a most particular embodiment, R⁴ is—NHC(═O)OCH₃, —NHC(═O)OCH₂CH₃, or —NHC(═O)OC(CH₃)₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —NHC(═O)R^(7e), and R^(7e) is as previouslydescribed. In a particular embodiment, R^(7e) is H. In anotherparticular embodiment, R^(7e) is C₁₋₄ alkyl. In yet another particularembodiment, R^(7e) is C₁₋₄ alkyl substituted with one OH, C₁₋₄ alkoxy.In a more particular embodiment, R^(7e) is Me, Et, iPr or tBu. Inanother more particular embodiment, R^(7e) is Me, Et, iPr or tBu, eachof which is substituted with one OH, C₁₋₄ alkoxy. In yet another moreparticular embodiment, R^(7e) is Me, Et, iPr or tBu, each of which issubstituted with one OH, —OCH₃. In a most particular embodiment, R⁴ is—NHC(═O)CH₃, —NHC(═O)CH₂CH₃, or —NHC(═O)C(CH₃)₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁴ is —NR^(8a)R^(8b), and each R^(8a) or R^(8b) is aspreviously described. In a particular embodiment, R^(8a) and R^(8b) areH. In another particular embodiment, one of R^(8a) or R^(8b) is H, andthe other is C₁₋₄ alkyl. In yet another particular embodiment, one ofR^(8a) or R^(8b) is H, and the other is C₁₋₄ alkyl substituted with oneOH, C₁₋₄ alkoxy, or phenyl. In a further particular embodiment, R^(8a)and R^(8b) are C₁₋₄ alkyl. In a more particular embodiment, one ofR^(8a) or R^(8b) is H, and the other is Me, Et, iPr or tBu. In anothermore particular embodiment, one of R^(8a) or R^(8b) is H, and the otheris Me, Et, iPr or tBu, each of which is substituted with one OH, C₁₋₄alkoxy, or phenyl. In yet another more particular embodiment, one ofR^(8a) or R^(8b) is H, and the other is Me, Et, iPr or tBu, each ofwhich is substituted with one OH, —OCH₃, or phenyl. In a most particularembodiment, R⁴ is —NH₂, —NHCH₃, —N(CH₃)₂, —NHCH₂Phenyl, or—NHCH₂CH₂—OCH₃.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is 4-7 membered monocyclic heterocycloalkylcomprising 1 to 2 heteroatoms independently selected from N, O, and S.In a particular embodiment, R¹ is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, ordioxanyl. In a more particular embodiment, R¹ is azetidinyl.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R¹ is 4-7 membered monocyclic heterocycloalkyl comprising1 to 2 heteroatoms independently selected from N, O, and S, substitutedwith one or more independently selected C₁₋₄ alkyl, —C(═O)C₁₋₄ alkyl, or—C(═O)OC₁₋₄ alkyl. In another embodiment, R¹ is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl, each of which is substituted with one ormore independently selected C₁₋₄ alkyl, —C(═O)C₁₋₄ alkyl, or —C(═O)OC₁₋₄alkyl. In a particular embodiment, R¹ is 4-7 membered monocyclicheterocycloalkyl comprising 1 to 2 heteroatoms independently selectedfrom N, O, and S, substituted with one C₁₋₄ alkyl, —C(═O)C₁₋₄ alkyl, or—C(═O)OC₁₋₄ alkyl. In another particular embodiment, R¹ is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl, each of which is substituted with oneC₁₋₄ alkyl, —C(═O)C₁₋₄ alkyl, or —C(═O)OC₁₋₄ alkyl. In a more particularembodiment, R¹ is 4-7 membered monocyclic heterocycloalkyl comprising 1to 2 heteroatoms independently selected from N, O, and S, substitutedwith one or more independently selected —CH₃, —C(═O)CH₃, or—C(═O)OC(CH₃)₃. In another more particular embodiment, R¹ is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or dioxanyl, each of which is substituted with one ormore independently selected —CH₃, —C(═O)CH₃, —C(═O)OCH₃, or—C(═O)OC(CH₃)₃. In yet another more particular embodiment, R¹ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which issubstituted with one —C(═O)CH₃, —C(═O)OCH₃, or —C(═O)OC(CH₃)₃.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R¹ is phenyl.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is phenyl substituted with one or moreindependently selected R⁵ groups. In a particular embodiment, R¹ isphenyl substituted with one, two, or three independently selected R⁵groups. In another particular embodiment, R¹ is phenyl substituted withone R⁵ group.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R¹ is 5-6 membered monocyclic heteroaryl comprising 1 or2 heteroatoms independently selected from N, O, and S. In a particularembodiment, R¹ is imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl,pyrimidinyl or pyrazinyl.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R¹ is 5-6 membered monocyclic heteroarylcomprising 1, 2 or 3 heteroatoms independently selected from N, O, and Ssubstituted with one or more independently selected R⁵ groups. Inanother embodiment R¹ is imidazolyl, pyrazolyl, thiazolyl, oxazolyl,pyridinyl, pyrimidinyl or pyrazinyl, each of which is substituted withone or more independently selected R⁵ groups. In a particularembodiment, R¹ is 5-6 membered monocyclic heteroaryl comprising 1, 2 or3 heteroatoms independently selected from N, O, and S substituted withone, two, or three independently selected R⁵ groups. In anotherparticular embodiment, R¹ is imidazolyl, pyrazolyl, thiazolyl, oxazolyl,pyridinyl, pyrimidinyl or pyrazinyl, each of which is substituted withone, two, or three independently selected R⁵ groups. In a moreparticular embodiment, R¹ is 5-6 membered monocyclic heteroarylcomprising 1, 2 or 3 heteroatoms independently selected from N, O, and Ssubstituted with one R⁵ group. In another more particular embodiment, R¹is imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl orpyrazinyl, each of which is substituted with one R⁵ group.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁵ is halo, OH, or CN. In a particular embodiment, R⁵ isF, Cl, OH, or CN.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁵ is C₁₋₄ alkyl. In a particular embodiment, R⁵ is Me,Et, or iPr.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R⁵ is C₁₋₄ alkyl substituted with one or moreindependently selected halo, —NR^(9a)R^(9b), —C(═O)NR^(9c)R^(9d),wherein R^(9a), R^(9b), R^(9c), or R^(9d) is as previously described. Inanother embodiment, R⁵ is Me, or Et, each of which is substituted withone or more independently selected halo, —NR^(9a)R^(9b),—C(═O)NR^(9c)R^(9d). In a particular embodiment, R⁵ is C₁₋₄ alkylsubstituted with one, two or three independently selected halo,—NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d). In another particularembodiment, R⁵ is Me, or Et, each of which is substituted with one, two,or three independently selected halo, —NR^(9a)R^(9b), or—C(═O)NR^(9c)R^(9d). In a more particular embodiment, R⁵ is C₁₋₄ alkylsubstituted with one halo, —NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d). Inanother more particular embodiment, R⁵ is Me, or Et, each of which issubstituted with one halo, —NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d). Inone embodiment, each R^(9a), R^(9b), R^(9c), or R^(9d) is independentlyselected from H, Me, and Et. In a most particular embodiment, R⁵ is—CF₃, —CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂C(═O)NH₂, —CH₂C(═O)NHMe, or—CH₂C(═O)NMe₂.

In one embodiment, a compound of the invention is according to Formula Ior II, wherein R⁵ is C₁₋₄ alkoxy. In a particular embodiment, R⁵ is—OMe,—OEt, or -OiPr.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R⁵ is C₁₋₄ alkoxy substituted with one—NR^(9e)R^(9f) wherein R^(9e) are R^(9f) as previously described. Inanother embodiment, R⁵ is—OEt, substituted with one —NR^(9e)R^(9f). Inone embodiment, each R^(9e), and R^(9f), is independently selected fromH, Me, and Et. In a most particular embodiment, R⁵ is —OCH₂CH₂NH₂,—OCH₂CH₂NHMe, or —OCH₂CH₂NMe₂.

In another embodiment, a compound of the invention is according toFormula I or II, wherein R⁵ is —S(═O)₂C₁₋₄ alkyl. In a particularembodiment, R⁵ is —S(═O)₂CH₃.

In one embodiment, a compound of the invention is according to FormulaIIIa or IIIb:

wherein R², R^(3a), R^(3b), R⁶, the subscript n and Cy are as describedabove.

In one embodiment, a compound of the invention is according to FormulaIIIc or IIId:

wherein R², R^(3a), R^(3b), R⁶, the subscript n and Cy are as describedabove.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is H.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is —OH.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is C₁₋₄ alkoxy. In a particularembodiment, R² is —OMe,—OEt, or -OiPr. In a more particular embodiment,R² is —OMe.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is C₁₋₄ alkyl. In a particularembodiment, R² is Me, Et, or iPr. In a more particular embodiment, R² isMe, or Et. In a most particular embodiment, R² is Me.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is C₁₋₄ alkyl substituted with one OH, orCN. In a particular embodiment, R² is Me, or Et, each of which issubstituted with one OH, or CN. In a more particular embodiment, R² is—CH₂—OH, or —CH₂—CN.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is C₁₋₄ alkyl substituted with one C₁₋₄alkoxy optionally substituted with one phenyl. In another embodiment, R²is Me, or Et, each of which is substituted with one C₁₋₄ alkoxyoptionally substituted with one phenyl. In a particular embodiment, R²is C₁₋₄ alkyl substituted with one —OMe,—OEt, each of which isoptionally substituted with one phenyl. In another particularembodiment, R² is Me, or Et, each of which is substituted with one—OMe,—OEt, each of which is optionally substituted with one phenyl. In amore particular embodiment, R² is —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂OCH₂CH₂OCH₃, or —CH₂OCH₂Phenyl.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IIId, wherein R² is C₁₋₄ alkyl substituted with one 5-6membered monocyclic heteroaryl comprising 1 or 2 heteroatomsindependently selected from N, O, and S, optionally substituted with oneor more independently selected C₁₋₄ alkyl. In another embodiment, R² isMe, or Et, each of which is substituted with one 5-6 membered monocyclicheteroaryl comprising 1 or 2 heteroatoms independently selected from N,O, and S, optionally substituted with one or more independently selectedC₁₋₄ alkyl. In a particular embodiment, R² is C₁₋₄ alkyl substitutedwith one imidazolyl, pyrrazolyl, oxazolyl, each of which is optionallysubstituted with one or more independently selected C₁₋₄ alkyl. Inanother particular embodiment, R² is Me or Et, each of which issubstituted with one imidazolyl, pyrrazolyl, oxazolyl, each of which isoptionally substituted with one or more independently selected C₁₋₄alkyl. In a more particular embodiment, R² is C₁₋₄ alkyl substitutedwith one imidazolyl, pyrrazolyl, oxazolyl, each of which is optionallysubstituted with one or more independently selected Me, or Et. Inanother particular embodiment, R² is Me, or Et, each of which issubstituted with one imidazolyl, pyrrazolyl, oxazolyl, each of which isoptionally substituted with one or more independently selected Me, orEt.

In one embodiment, a compound of the invention is according to FormulaIVa or IVb:

wherein R^(3a), R^(3b), R⁶, the subscript n and Cy are as describedabove.

In one embodiment, a compound of the invention is according to FormulaIVc or IVd:

wherein R^(3a), R^(3b), R⁶, the subscript n and Cy are as describedabove.

In one embodiment, a compound of the invention is according to any oneof Formulae I-IVd, wherein R^(3a), and R^(3b) are both H. In anotherembodiment, one of R^(3a) and R^(3b) is H, and the other is C₁₋₄ alkyloptionally substituted with one or more halo. In a particularembodiment, one of R^(3a) and R^(3b) is H, and the other is Me or Etoptionally substituted with one or more halo. In another particularembodiment, one of R^(3a) and R^(3b) is H, and the other is Me or Et. Ina more particular embodiment, one of R^(3a) and R^(3b) is H, and theother is Me, Et or CF₃. In a most particular embodiment, one of R^(3a)and R^(3b) is H, and the other is Me. In another most particularembodiment, one of R^(3a) and R^(3b) is H, and the other is CF₃. Inanother most particular embodiment, R^(3a) and R^(3b) are both Me.

In one embodiment, a compound of the invention is according to FormulaVa or Vb:

wherein R^(3b), R⁶, the subscript n and Cy are as described above.

In one embodiment, a compound of the invention is according to FormulaVc or Vd:

wherein R^(3b), R⁶, the subscript n and Cy are as described above.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein Cy is 6-10 membered monocyclic or fusedbicyclic aryl. In a particular embodiment, Cy is phenyl, or naphthyl. Ina more particular embodiment, Cy is phenyl.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein Cy is 5-10 membered monocyclic or fusedbicyclic heteroaryl comprising 1, 2 or 3 heteroatoms independentlyselected from N, O, and S. In a particular embodiment, Cy is pyrrazolyl,oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, indolyl, indazolyl, pyrrolopyridinyl, or benzofuranyl. In amore particular embodiment, Cy is pyridinyl.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein the subscript n is 0.

In another embodiment, a compound of the invention is according to anyone of Formulae I-Vd, wherein the subscript n is 1, 2 or 3. In aparticular embodiment, the subscript n is 1 or 2.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein R⁶ is halo, —CN, —NO₂, C₁₋₄ alkyl optionallysubstituted with one or more halo, or C₁₋₄ alkoxy optionally substitutedwith one or more halo. In a particular embodiment, R⁶ is halo, C₁₋₄alkyl, or C₁₋₄ alkoxy. In a more particular embodiment, R⁶ is F, Cl,—CH₃, —CH₂CH₃—CF₃, —OCH₃, —OCH₂CH₃, or —OCF₃. In a most particularembodiment, R⁶ is F, Cl, —CH₃, or —OCH₃.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein R⁶ is 5-10 membered monocyclic or fusedbicyclic heteroaryl comprising 1, 2 or 3 heteroatoms independentlyselected from N, O, and S, optionally substituted with one or moreindependently selected halo, C₁₋₄ alkyl, C₁₋₄ alkoxy. In anotherembodiment, R⁶ is pyrrazolyl, oxazolyl, oxadiazolyl, thiazolyl,pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which isoptionally substituted with one or more independently selected halo,C₁₋₄ alkyl, C₁₋₄ alkoxy. In a particular embodiment, R⁶ is 5-10 memberedmonocyclic or fused bicyclic heteroaryl comprising 1, 2 or 3 heteroatomsindependently selected from N, O, and S, optionally substituted withone, two, or three independently selected halo, C₁₋₄ alkyl, or C₁₋₄alkoxy. In another particular embodiment, R⁶ is pyrrazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridazinyl, orpyrimidinyl, each of which is optionally substituted with one, two, orthree independently selected halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy. In a moreparticular embodiment, R⁶ is 5-10 membered monocyclic or fused bicyclicheteroaryl comprising 1, 2 or 3 heteroatoms independently selected fromN, O, and S, optionally substituted with one halo, C₁₋₄ alkyl, C₁₋₄alkoxy. In another more particular embodiment, R⁶ is pyrrazolyl,oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridazinyl, orpyrimidinyl, each of which is optionally substituted with one halo, C₁₋₄alkyl, or C₁₋₄ alkoxy. In a most particular embodiment, R⁶ is 5-10membered monocyclic or fused bicyclic heteroaryl comprising 1, 2 or 3heteroatoms independently selected from N, O, and S, optionallysubstituted with one, two, or three independently selected F, Cl, Me,Et, —OMe, or -OEt. In another more particular embodiment, R⁶ ispyrrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl,pyridazinyl, or pyrimidinyl, each of which is optionally substitutedwith one, two, or three independently selected F, Cl, Me, Et, —OMe, or-OEt.

In one embodiment, a compound of the invention is according to any oneof Formulae I-Vd, wherein R⁶ is —NR^(9g)R^(9h), wherein R^(9g) andR^(9h) are as previously described. In a particular embodiment, R^(9g)and R^(9h) are both H. In another particular embodiment, R^(9g) andR^(9h) are both C₁₋₄ alkyl. In yet another particular embodiment, one ofR^(9g) and R^(9h) is H, and the other is C₁₋₄ alkyl. In a moreparticular embodiment, R⁶ is —NH₂, —NHMe, or —NMe₂.

In one embodiment, a compound of the invention is according to any oneof Formulae Va-Vd, wherein R^(3b) is H.

In one embodiment, a compound of the invention is according to any oneof Formulae Va-Vd, wherein R^(3b) is —CH₃.

In one embodiment, a compound of the invention is according to FormulaI-Vd, wherein the

moiety is

wherein each R^(6a), R^(6b) and R^(6c) is independently selected from H,halo, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy. In a particularembodiment, each R^(6a), R^(6b) and R^(6c) is independently selectedfrom H, F, Cl, —CN, —CH₃, —CH₂CH₃, —OCH₃, and —OCH₂CH₃. In a moreparticular embodiment, each R^(h)a is H, and each R^(6b) and R^(6c) isindependently selected from H, F, Cl, —CN, —CH₃, —CH₂CH₃, —OCH₃, and—OCH₂CH₃. In a most particular embodiment, each R^(h)a is H, and eachR^(6b) and R^(6c) is independently selected from H, F, Cl, —CH₃, and—OCH₃.

In one embodiment, a compound of the invention is selected from:

-   5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-[3-oxo-3-(4-phenyl-1-piperidyl)propyl]imidazolidine-2,4-dione,-   5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)-5-phenylimidazolidine-2,4-dione,-   5-methyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-isopropyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-(3-(4-(2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-cyclopropyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-methyl-5-(3-oxo-3-(4-p-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-(3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(4-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(4-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(2-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-methyl-5-(3-oxo-3-(4-m-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)-5-(pyridin-3-yl)imidazolidine-2,4-dione,-   5-cyclopropyl-5-(3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione,-   5-cyclopropyl-5-(3-(4-(3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (S)-5-cyclopropyl-5-((S)-2-methyl-3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-methyl-5-((S)-2-methyl-3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   (R)-5-((S)-3-(4-(4-chlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-((S)-3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-((S)-3-(4-(4-fluorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-methyl-5-((S)-2-methyl-3-oxo-3-(4-m-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   (R)-5-((S)-3-(4-(3-fluorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-((S)-3-(4-(3-chlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-5-methoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(2,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-5-methoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(2,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,4-difluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3,4-difluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(3,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-fluoro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,4-difluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(4-fluoro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3,4-difluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-methyl-5-(3-oxo-3-(4-o-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   (R)-5-(3-oxo-3-(4-o-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(4-chloro-5-fluoro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4-chloro-5-fluoro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3-chloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3-chloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,4-dichloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,4-dichloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (R)-5-(3-(4-(3,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(4,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(4-fluoro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-(3-(4-(3-chloro-4-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   (R)-5-(3-(4-(3-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   5-(3-(4-(3-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,-   5-cyclopropyl-5-(3-((3R,4R)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-O-3-oxopropyl)imidazolidine-2,4-dione,-   (S)-5-cyclopropyl-5-(3-((3R,4S)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (S)-5-cyclopropyl-5-(3-((3R,4R)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(3-chloro-4-fluoro-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-fluoro-3,5-dimethoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-fluoro-3,5-dimethoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-fluoro-5-methoxy-2-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(3-chloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-ethoxy-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-ethoxy-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-2-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-[4-chloro-3-(dimethylamino)-5-methoxy-phenyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-[4-chloro-3-(dimethylamino)-5-methoxy-phenyl]-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,-   5-[3[4-(4,5-dichloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-(6-methyl-2-pyridyl)imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3,5-dimethyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-[4-chloro-3-(trifluoromethyl)phenyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4,5-dichloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[(2S)-3-[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[(3R,4R)-4-(3,4-difluorophenyl)-3-methyl-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[(2S)-3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,-   (5R)-5-[(2S)-3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[(2S)-3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   5-[3-[4-[5-(2-fluorophenyl)-2-thienyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5R)-5-[(2S)-3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,-   (5S)-5-[(2S)-3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione    (5R)-5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,-   (5R)-5-[(2R)-3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,    and-   (5S)-5-[(2R)-3-[4-(4-chloro-3-fluoro-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-(methoxymethyl)imidazolidine-2,4-dione.

In one embodiment a compound of the invention is not an isotopicvariant.

In one aspect a compound of the invention according to any one of theembodiments herein described is present as the free base.

In one aspect a compound of the invention according to any one of theembodiments herein described is a pharmaceutically acceptable salt.

In one aspect a compound of the invention according to any one of theembodiments herein described is a solvate of the compound.

In one aspect a compound of the invention according to any one of theembodiments herein described is a solvate of a pharmaceuticallyacceptable salt of a compound.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention includes one in whichseveral or each embodiment in the above Formula, as well as otherformulae presented herein, is selected from one or more of particularmembers or groups designated respectively, for each variable. Therefore,this invention is intended to include all combinations of suchembodiments within its scope.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention may be one for which oneor more variables (for example, R groups) is selected from one or moreembodiments according to any of the Formula (e) listed above. Therefore,the present invention is intended to include all combinations ofvariables from any of the disclosed embodiments within its scope.

Alternatively, the exclusion of one or more of the specified variablesfrom a group or an embodiment, or combinations thereof is alsocontemplated by the present invention.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds according to the formulae above. Prodrugsare derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (Bundgard, H, 1985). Prodrugs includeacid derivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C₁ to C₈alkyl, C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂arylalkyl esters of the compounds of the invention.

Pharmaceutical Compositions

When employed as a pharmaceutical, a compound of the invention istypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound of theinvention according to Formula I. Generally, a compound of the inventionis administered in a pharmaceutically effective amount. The amount ofcompound of the invention actually administered will typically bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound of the invention administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The pharmaceutical compositions of this invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intra-articular, intravenous, intramuscular, and intranasal. Dependingon the intended route of delivery, a compound of the invention ispreferably formulated as either injectable or oral compositions or assalves, as lotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term ‘unit dosage forms’ refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient, vehicle orcarrier. Typical unit dosage forms include prefilled, premeasuredampules or syringes of the liquid compositions or pills, tablets,capsules or the like in the case of solid compositions. In suchcompositions, the compound of the invention according to Formula I isusually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or non-aqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compound of the inventionsof a similar nature: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, or corn starch; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; a sweetening agent such as sucrose or saccharin; or aflavoring agent such as peppermint or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound of the invention according toFormula I in such compositions is typically a minor component, oftenbeing from about 0.05 to 10% by weight with the remainder being theinjectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as an ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

A compound of the invention can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17^(th) edition, 1985,Mack Publishing Company, Easton, Pa., which is incorporated herein byreference.

A compound of the invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Formulation 1—Tablets

A compound of the invention according to Formula I may be admixed as adry powder with a dry gelatin binder in an approximate 1:2 weight ratio.A minor amount of magnesium stearate may be added as a lubricant. Themixture may be formed into 240-270 mg tablets (80-90 mg of activecompound of the invention according to Formula I per tablet) in a tabletpress.

Formulation 2—Capsules

A compound of the invention according to Formula I may be admixed as adry powder with a starch diluent in an approximate 1:1 weight ratio. Themixture may be filled into 250 mg capsules (125 mg of active compound ofthe invention according to Formula I per capsule).

Formulation 3—Liquid

A compound of the invention according to Formula I (125 mg), may beadmixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultantmixture may be blended, passed through a No. 10 mesh U.S. sieve, andthen mixed with a previously made solution of microcrystalline celluloseand sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodiumbenzoate (10 mg), flavor, and color may be diluted with water and addedwith stirring. Sufficient water may then be added with stirring. Furthersufficient water may be then added to produce a total volume of 5 mL.

Formulation 4 —Tablets

A compound of the invention according to Formula I may be admixed as adry powder with a dry gelatin binder in an approximate 1:2 weight ratio.A minor amount of magnesium stearate may be added as a lubricant. Themixture may be formed into 450-900 mg tablets (150-300 mg of activecompound of the invention according to Formula I) in a tablet press.

Formulation 5—Injection

A compound of the invention according to Formula I may be dissolved orsuspended in a buffered sterile saline injectable aqueous medium to aconcentration of approximately 5 mg/mL.

Formulation 6—Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted atabout 75° C. and then a mixture of A compound of the invention accordingto Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g),sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved inwater (about 370 g) may be added and the resulting mixture may bestirred until it congeals.

Methods of Treatment

In one embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention, for use in medicine. In a particular embodiment, the presentinvention provides compounds of the invention or pharmaceuticalcompositions comprising a compound of the invention, for use in theprophylaxis and/or treatment of inflammatory diseases, and/or diseasesinvolving degradation of cartilage and/or disruption of cartilagehomeostasis.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of inflammatory diseases, and/or diseasesinvolving degradation of cartilage and/or disruption of cartilagehomeostasis.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, and anothertherapeutic agent. In a particular embodiment, the other therapeuticagent is an agent for the prophylaxis and/or treatment of inflammatorydiseases, and/or diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of inflammatory diseases, and/ordiseases involving degradation of cartilage and/or disruption ofcartilage homeostasis, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withinflammatory diseases, and/or diseases involving degradation ofcartilage and/or disruption of cartilage homeostasis, which methodscomprise the administration of an effective amount of a compound of theinvention or one or more of the pharmaceutical compositions hereindescribed for the treatment or prophylaxis of said condition.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of inflammatorydiseases. In a particular embodiment, the inflammatory disease isselected from rheumatoid arthritis, and osteoarthritis. Moreparticularly, the inflammatory disease is osteoarthritis.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of inflammatory diseases. In a particularembodiment, the inflammatory disease is selected from rheumatoidarthritis, and osteoarthritis. More particularly, the inflammatorydisease is osteoarthritis.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withinflammatory diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, theinflammatory disease is selected from rheumatoid arthritis, andosteoarthritis. More particularly, the inflammatory disease isosteoarthritis.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of diseasesinvolving degradation of cartilage and/or disruption of cartilagehomeostasis. In a particular embodiment, the diseases involvingdegradation of cartilage and/or disruption of cartilage homeostasis isselected from osteoarthritis, psoriatic arthritis, juvenile rheumatoidarthritis, gouty arthritis, septic or infectious arthritis, reactivearthritis, reflex sympathetic dystrophy, algodystrophy, achondroplasia,Paget's disease, Tietze syndrome or costal chondritis, fibromyalgia,osteochondritis, neurogenic or neuropathic arthritis, arthropathy,sarcoidosis, amylosis, hydarthrosis, periodical disease, rheumatoidspondylitis, endemic forms of arthritis like osteoarthritis deformansendemica, Mseleni disease and Handigodu disease; degeneration resultingfrom fibromyalgia, systemic lupus erythematosus, scleroderma andankylosing spondylitis. More particularly, the diseases involvingdegradation of cartilage and/or disruption of cartilage homeostasis isosteoarthritis (OA).

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of diseases involving degradation ofcartilage and/or disruption of cartilage homeostasis. In a particularembodiment, the diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis is selected from osteoarthritis,psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis,septic or infectious arthritis, reactive arthritis, reflex sympatheticdystrophy, algodystrophy, achondroplasia, Paget's disease, Tietzesyndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenicor neuropathic arthritis, arthropathy, sarcoidosis, amylosis,hydarthrosis, periodical disease, rheumatoid spondylitis, endemic formsof arthritis like osteoarthritis deformans endemica, Mseleni disease andHandigodu disease; degeneration resulting from fibromyalgia, systemiclupus erythematosus, scleroderma and ankylosing spondylitis. Moreparticularly, the diseases involving degradation of cartilage and/ordisruption of cartilage homeostasis is osteoarthritis (OA).

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withdiseases involving degradation of cartilage and/or disruption ofcartilage homeostasis, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, the diseasesinvolving degradation of cartilage and/or disruption of cartilagehomeostasis is selected from osteoarthritis, psoriatic arthritis,juvenile rheumatoid arthritis, gouty arthritis, septic or infectiousarthritis, reactive arthritis, reflex sympathetic dystrophy,algodystrophy, achondroplasia, Paget's disease, Tietze syndrome orcostal chondritis, fibromyalgia, osteochondritis, neurogenic orneuropathic arthritis, arthropathy, sarcoidosis, amylosis, hydarthrosis,periodical disease, rheumatoid spondylitis, endemic forms of arthritislike osteoarthritis deformans endemica, Mseleni disease and Handigodudisease; degeneration resulting from fibromyalgia, systemic lupuserythematosus, scleroderma and ankylosing spondylitis. More particularlythe diseases involving degradation of cartilage and/or disruption ofcartilage homeostasis is osteoarthritis (OA).

Injection dose levels range from about 0.1 mg/kg/h to at least 10mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more mayalso be administered to achieve adequate steady state levels. Themaximum total dose is not expected to exceed about 1 g/day for a 40 to80 kg human patient.

For the prophylaxis and/or treatment of long-term conditions, such asdegenerative conditions, the regimen for treatment usually stretchesover many months or years so oral dosing is preferred for patientconvenience and tolerance. With oral dosing, one to four (1-4) regulardoses daily, especially one to three (1-3) regular doses daily,typically one to two (1-2) regular doses daily, and most typically one(1) regular dose daily are representative regimens. Alternatively forlong lasting effect drugs, with oral dosing, once every other week, onceweekly, and once a day are representative regimens. In particular,dosage regimen can be every 1-14 days, more particularly 1-10 days, evenmore particularly 1-7 days, and most particularly 1-3 days.

Using these dosing patterns, each dose provides from about 1 to about1000 mg of a compound of the invention, with particular doses eachproviding from about 10 to about 500 mg and especially about 30 to about250 mg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a condition, a compound of theinvention will be administered to a patient at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

A compound of the invention can be administered as the sole active agentor it can be administered in combination with other therapeutic agents,including other compound of the inventions that demonstrate the same ora similar therapeutic activity and that are determined to be safe andefficacious for such combined administration. In a specific embodiment,co-administration of two (or more) agents allows for significantly lowerdoses of each to be used, thereby reducing the side effects seen.

In one embodiment, a compound of the invention or a pharmaceuticalcomposition comprising a compound of the invention is administered as amedicament. In a specific embodiment, said pharmaceutical compositionadditionally comprises a further active ingredient.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis of adisease involving inflammation, particular agents include, but are notlimited to, immunoregulatory agents e.g. azathioprine, corticosteroids(e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A,tacrolimus, mycophenolate, mofetil, muromonab-CD3 (OKT3, e.g.Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, andpiroxicam.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofarthritis (e.g. rheumatoid arthritis), particular agents include but arenot limited to analgesics, non-steroidal anti-inflammatory drugs(NSAIDS), steroids, synthetic DMARDS (for example but without limitationmethotrexate, leflunomide, sulfasalazine, Auranofin, sodiumaurothiomalate, penicillamine, chloroquine, hydroxychloroquine,azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin),and biological DMARDS (for example but without limitation infliximab,etanercept, adalimumab, rituximab, and abatacept).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis of SLE,particular agents include but are not limited to: human monoclonalantibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs(DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine),immunosuppressants (e.g. methotrexate and azathioprine),cyclophosphamide and mycophenolic acid, immunosuppressive drugs andanalgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g.dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone,oxycodone, MS Contin, or methadone) and the fentanyl duragesictransdermal patch.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofpsoriasis, particular agents include but are not limited to: topicaltreatments such as bath solutions, moisturizers, medicated creams andointments containing coal tar, dithranol (anthralin), corticosteroidslike desoximetasone (Topicort™), fluocinonide, vitamin D3 analogues (forexample, calcipotriol), argan oil and retinoids (etretinate, acitretin,tazarotene), systemic treatments such as methotrexate, cyclosporine,retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolatemofetil, azathioprine, tacrolimus, fumaric acid esters or biologics suchas Amevive™ Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (aIL-12 and IL-23 blocker). Additionally, a compound of the invention maybe administered in combination with other therapies including, but notlimited to phototherapy, or photochemotherapy (e.g. psoralen andultraviolet A phototherapy (PUVA)).

By co-administration is included any means of delivering two or moretherapeutic agents to the patient as part of the same treatment regime,as will be apparent to the skilled person. Whilst the two or more agentsmay be administered simultaneously in a single formulation, i.e. as asingle pharmaceutical composition, this is not essential. The agents maybe administered in different formulations and at different times.

Chemical Synthetic Procedures General

The compound of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants,solvents, pressures, etc.) are given, other process conditions can alsobe used unless otherwise stated. Optimum reaction conditions may varywith the particular reactants or solvent used, but such conditions canbe determined by one skilled in the art by routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art (Greene, T W; Wuts, P G M, 1991).

The following methods are presented with details as to the preparationof a compound of the invention as defined hereinabove and thecomparative examples. A compound of the invention may be prepared fromknown or commercially available starting materials and reagents by oneskilled in the art of organic synthesis.

All reagents are of commercial grade and are used as received withoutfurther purification, unless otherwise stated. Commercially availableanhydrous solvents are used for reactions conducted under inertatmosphere. Reagent grade solvents are used in all other cases, unlessotherwise specified. Column chromatography is performed on silica gel 60(35-70 μm). Thin layer chromatography is carried out using pre-coatedsilica gel 60E-254 plates (thickness 0.25 mm). ¹H NMR spectra arerecorded on a 400 MHz Avance Bruker spectrometer or a 300 MHz DPX Brukerspectrometer. Chemical shifts (δ) for ¹H NMR spectra are reported inparts per million (ppm) relative to tetramethylsilane (δ 0.00) or theappropriate residual solvent peak, i.e. CHCl₃ (δ 7.27), as internalreference. Multiplicities are given as singlet (s), doublet (d), triplet(t), quartet (q), quintuplet (quin), multiplet (m) and broad (br).Electrospray MS spectra are obtained on a Waters platform LC/MSspectrometer or with Waters Acquity UPLC with Waters Acquity PDAdetector and SQD mass spectrometer. Columns used: UPLC BEH C18 1.7 μm2.1×5 mm VanGuard Pre-column with Acquity UPLC BEH C18 1.7 μm 2.1×30 mmColumn or Acquity UPLC BEH C18 1.7 μm 2.1×50 mm Column. All the methodsare using MeCN/H₂O gradients. MeCN and H₂O contain either 0.1% FormicAcid or 0.05% NH₃. Preparative LCMS: column used, Waters XBridge PrepC18 5 μm ODB 30 mm ID×100 mm L (preparative column) and Waters XBridgeC18 5 μm 4.6 mm ID×100 mm L (analytical column). All the methods areusing MeCN/H₂O gradients. MeCN and H₂O contain either 0.1% Formic Acidor 0.1% Diethylamine. Chiral HPLC analysis are obtained from a Waters2690 Alliance HPLC system. Microwave heating is performed with a BiotageInitiator. Optical rotation was determined on a Dr. Kernchen Propoldigital automatic polarimeter.

TABLE I List of abbreviations used in the experimental section:Abbreviation Definition μL microliter AUC Area Under the Curve BINAP2,2′-Bis(diphenylphosphino)- 1,1′-binaphthalene Bn Benzyl br. D Broaddoublet Boc tert-Butyloxy-carbonyl BOP (Benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate br. S Broadsinglet br. T Broad triplet Cat. Catalytic amount CDI1,1′-Carbonyldiimidazole COCl₂ Phosgene Cpd Compound d doublet DavePhos2-Dicyclohexylphosphino-2′- (N,N-dime thylamino)biphenyl DCM DCM DEADDiethyl azodicarboxylate DIPE Diisopropylether DIPEAN,N-diisopropylethylamine DMA Dime thylacetamide DMAP4-Dimethylaminopyridine DME Dimethoxyethane DMF N,N-dimethylformamideDMPU 1,3-Dimethy1-3,4,5,6- tetrahydro-2(1H)-pyrimidinone DMSODimethylsulfoxide Dppf 1,1′- Bis( diphenylphosphino) ferrocene EDC1-ethy1-3-(3- dimethylaminopropyl) carbodiimide) EDC.HClN-(3-Dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride eq.Equivalent Et₃N Triethylamine Et₂O Diethyl ether EtOAc Ethyl acetateEtOH Ethanol FBS Fetal bovine serum g gram h hour HATUO-(7-azabenzotriazol-1-yl)- N,N,N′,N′-tetramethyluroniumhexafluorophosphate HOBt Hydroxybenzotriazole HPLC High-performanceliquid chromatography HPLC/MS High-performance liquidchromatography/mass- spectrometry HRMS High-resolution Mass SpectrometryHRP horseradish peroxydase Int Intermediate JohnPhos(2-Biphenyl)di-tert- butylphosphine kg kilogram L liter LCMS LiquidChromatography- Mass Spectrometry LDA Lithium diisopropylamide LiHMDSLithium bis (trimethylsilyl)amide m multiplet m-CPBA 3-Chloroperbenzoicacid MeCN Acetonitrile MEK Methyl ethyl ketone Meldrum's2,2-dimethyl-1,3-dioxane-4,6- acid dione MeOH Methanol Mg milligram Minminute mL millilitre mmol millimoles MMP Matrix Metallo Proteinase Ms'dMass measured by LCMS Mtd Method Mukaiyama 2-Chloro-1-methylpyridiniumreagent iodide MW Molecular weight N.A. Not available n/a No measurableactivity Nva Norvaline iPrOH Isopropyl alcohol nBuOH n-Butanol NMRNuclear Magnetic PBF phosphate buffered formalin PBS Phosphate bufferedsalin P(tBu)₃ Tristertbutylphosphine P(Bu)₃ Tributylphosphine Pd(PPh₃)₄Tetrakis(triphenylphosphine)pa lladium(0) Pd/C Palladium on Carbon 10%Pd²(dba)₃ Tris(dibenzylideneacetone) dipalladium(0) PdCl₂(dppf) [1,1′-Bis(diphenylphosphino)ferroce ne] dichloropalladium(II) PdCl₂[P(o-Dichlorobis(tri-o- Tol)₃]₂ tolylphosphine)palladium(II) Pd(OAc)₂Palladium(II) acetate Pd(OH)₂/C Palladium hydroxide on carbon PEGPolyethylene glycol PEPPS ™-IPr [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2- ylidene] (3-chloropyridyl) palladium(II)dichloride Ppm part-per-million PS-CDI Polymer supported 1,1′-Carbonyldiimidazole PS- Polymer supported Mukaiyama Mukaiyama reagentreagent q quadruplet r.t. room temperature RNA Ribonucleic acid Rtretention time RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl s singlet SCX Biotage Isolute ® SCX(BiotagePart 530) SCX-2 Biotage Isolute ® SCX-2 (Biotage Part 532) septseptuplet SFC Supercritical fluid chromatography SM Starting MaterialSter Stereochemistry t triplet TBAF Tetra-n-butylammonium fluoride5(6)-TAMRA 5(6)- Carboxytetramethylrhodamine (CAS# 98181-63-6) 5-FAM5-carboxyfluorescein (CAS# 76823-03-5) t-BuOH Tert-butanol TBDPSClTert-butyldiphenylsilyl chloride TBSCl Tert-butyldimethylsilyl chlorideTEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLCThin-layer chromatography TIPS triisopropyl silyl UPLC/MSUltra-performance liquid chromatography/mass-spectrometry spectrometryXantPhos 4,5-Bis(diphenylphosphino)- 9,9-dimethylxanthene XPhos2-Dicyclohexylphosphino- 2′,4′,6′-triisopropylbiphenyl MS Mass PDAPhotodiode array quin Quintet tBu Tert-butyl t-BuLi Tert-butyl lithiumUPLC Ultra Performance Liquid Chromatography

Example 1. Synthetic Preparation of the Compounds of the Invention 1.1.General Synthetic Methods 1.1.1. Synthetic Methods Overview

B: Preparation of Ketoester

C: Preparation of Ketoacid

General Methods a 1: Preparation of Arylpiperidine Via Suzuki Coupling

Method A1: Suzuki Reaction

Method A2: Hydrogenation

Method A3: Neigishi reaction

Method A4: Boc deprotection

-   -   Method A4a: with HCl in dioxane    -   Method A4b: with aqueous HCl    -   Method A4c: with HCl in dioxane+basic work-up

Method A5: Synthesis of substituted piperidine

General Methods B: Preparation of Ketoester

Method B1: from Meldrum's acid

Method B2: with tert-butyl bromoacetate

Method B3: Stetter reaction

General Method C: Preparation of Ketoacids

General Method D: Bucherer Bergs Reaction

General Method E: Method for Preparation of Hydantoin Propionic Acids

General Method F: Amide Bond Formation

Method F1: EDC/HOBt

Method F2: HATU

Method F3: BOP

Method F4: Mukaiyama Reagent

1.1.2. General Methods A: Preparation of Arylpiperidine 1.1.2.1. MethodA1: Suzuki Reaction

A solution of halogeno derivative (1 eq.) andN-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1 to 1.2eq.) in a mixture of dioxane and saturated aqueous NaHCO₃, is degassedwith nitrogen. Pd(PPh₃)₄ (0.05 eq. to 0.1 eq.) is added, and thereaction is stirred at 90° C. for 2 to 24 h. The reaction mixture ispoured in water and DCM. The organic layer is washed with water andconcentrated in vacuo to afford the expected arylpiperazine, to bepurified by flash chromatography on silica gel.

Illustrative Synthesis of Int 94

5-bromo-2-chloro-1-fluoro-3-methoxy-benzene (32 g, 134 mmol, 1.0 eq) andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(41.5 g, 134 mmol, 1.0 eq) are stirred at room temperature in a mixtureof dioxane (880 mL) and saturated aqueous NaHCO₃ (250 mL), in a roundbottom flask, and nitrogen is bubbled through the solution for 30 min.Pd(PPh₃)₄ (7.7 g, 6.7 mmol, 0.05 eq) is then added, and nitrogen is thenbubbled through the solution for a few more min, and the mixture is thenheated at 90° C. under nitrogen atmosphere. After 24 h, LC/MS analysisshows incomplete conversion. Pd(PPh₃)₄ (1.5 g) and boronic ester (1.5 g)are then newly added, and the mixture is stirred at 90° C. for theweekend.

Once complete conversion is observed by LC/MS analysis, the mixture isthen cooled back at room temperature, and concentrated under reducedpressure. The residue obtained is then partitioned between DCM andwater. The aqueous phase is extracted several times with DCM. Thecombined extracts are then dried and concentrated under reduced pressureto give crude expected compound that is then purified by flashchromatography (eluting with Heptane/AcOEt from 100/0 to 80/20), tofinally afford pure expected compound. LCMS: MW (calcd): 341; m/z MW(obsd): 286-288 (M+H−tBu).

1.1.2.2. Method A2: Hydrogenation

To a solution of N-boc aryl tetrahydropyridine (1 eq.) in EtOAc or MeOH,is added PtO₂ (0.1 to 0.3 eq). After purging with vacuum/hydrogenfilling cycles, the mixture is stirred under hydrogen atmosphere at roomtemperature for 3 to 24 h. The mixture is then filtered, and thefiltrate is concentrated under reduced pressure to afford clean expectedcompound, used directly in the next step without further purification.Illustrative Synthesis of Int 63

To a solution of Int 94 (40.8 g, 119 mmol, 1.0 eq) in ethyl acetate isadded PtO₂ (4.1 g, 18 mmol, 0.15 eq). After purging with variousvacuum/hydrogen filling cycles, the mixture was stirred under hydrogenatmosphere (2 balloons) at room temperature overnight. After completeconversion is observed (monitored by LC/MS analysis), the mixture isthen filtered, and the filtrate is concentrated under reduced pressure,then dissolved in minimum amount of DCM, filtered again, andconcentrated under reduced pressure to give clean expected compound useddirectly in the next step. LCMS: MW (calcd): 343; m/z MW (obsd): 288-290(M+H−tBu).

1.1.3. Method A3: Neigishi Reaction

Step i)

Zinc dust (521 mg, 8.0 mmol, 1.25 eq) and Celpure 65 (100 mg) aresuspended in DMA (1.3 mL). The mixture is then degassed under vacuum,and filled with argon. A trimethylsilyl chloride/1,2-dibromoethanemixture (7:5, V:V, 150 μL) is added dropwise, and the reaction mixtureis stirred for 15 min at room temperature. The N-Boc protectediodopiperidine (2 g, 6.4 mmol, 1 eq.) in DMA (3.2 mL) is added to theprevious solution dropwise, over 15 min under argon. The reaction isthen stirred at room temperature for 1 h. Stirring is then stopped forthe solid to settle at the bottom of the flask for 2 h. The solution wassyringed out, filtered into a sealed tube, purged with argon, and keptat room temperature, as a 1 M solution, for next coupling step.

Step ii)

A solution of bromo aryl derivative (1 eq),1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex(0.1 eq), copper (I) iodide (0.25 eq.) in DMA is degassed under vacuum,and filled with nitrogen. The 1 M solution of zinc reagent previouslymade is then added (1.4 eq.). The mixture is degassed one more time,heated at 80° C. for 3 h, and then at room temperature overnight. Thereaction is then quenched with brine, and ethyl acetate is added. Themixture is filtered through clarcel, and the aqueous layer is extractedwith ethyl acetate, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude compound is then purifiedby flash chromatography.

Step ii) Illustrative Synthesis of Int 55

A solution of 1-bromo-3,5-dimethoxy-4-chloro benzene (85 mg, 0.34 mmol,1.0 eq.), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichlorideDCM complex (25 mg, 0.034 mmol, 0.1 eq.), copper (I) iodide (16 mg,0.034 mmol, 0.25 eq.) in DMA (0.5 mL) is degassed under vacuum, andfilled with nitrogen. The 1 M solution of zinc reagent previously madeis then added (0.47 mL, 0.47 mmol, 1.4 eq.). The mixture is degassed onemore time, heated at 80° C. for 3 h, and then at room temperatureovernight. The reaction is then quenched with brine, and ethyl acetateis added. The mixture is filtered through clarcel, and the aqueous layeris extracted with ethyl acetate, dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The crude compound is thenpurified by flash chromatography (eluting with Heptane/EtOAc 100/0 to80/20) to afford the expected N-Boc aryl piperidine. LCMS: MW (calcd):366; m/z MW (obsd): 300 (M+H−tBu).

1.1.3.1. Method A4: Boc-Deprotection

1.1.3.1.1 Method A4a (with HCl in Dioxane)

A flask is charged with N-tert-butoxycarbonyl derivative (1 eq.), HCl 4Nin dioxane (10 to 40 eq.) is added. The reaction mixture can be dilutedwith DCM or dioxane, and stirred at r.t. for 1 h to 2 days. If aprecipitate is formed, it is filtered or centrifuged and washed withEt₂O or CH₃CN, otherwise, the reaction mixture is concentrated in vacuo.Both work-up afford the expected arylpiperidine as hydrochloride salt.

Illustrative Synthesis of Int 24

Int 63 (119 mmol, crude from previous step—see method A2) is stirred atroom temperature in HCl (4N) in dioxane. After 5-10 min at roomtemperature, the mixture is cooled with an ice/water bath, causingprecipitation of the compound, and when the temperature is stabilized,stirring is kept for 90 min at room temperature. The suspension obtainedis filtered, washed with dioxane, and dried under suction and then underreduced pressure to give clean expected compound as a chlorhydrate salt.LCMS: MW (calcd): 243; m/z MW (obsd): 244-246 (M+H).

1.1.3.1.2 Method A4b (with Aqueous HCl)

A flask is charged with N-tert-butoxycarbonyl derivative (1 eq.), andconcentrated aqueous HCl (37%) (200 eq.). The mixture is stirred at roomtemperature overnight, and if conversion is not completed, is thenheated at 80° C. for 1 h. After complete conversion is obtained, themixture is diluted with water (10 fold), and ethyl acetate is added. Theaqueous phase is collected, made basic by addition of solid NaOH (210eq.), and extracted with DCM. The organic phase is then collected,washed with brine, and dried over MgSO₄. After filtration, volatiles areremoved from the filtrate via rotary evaporation to give the expectedarylpiperidine.

Illustrative Synthesis of Int 47

A round bottomed flask (50 mL) is charged with Int 84 (0.210 g, 0.611mmol) and concentrated aqueous HCl (37%, 10 mL, 120 mmol, 200 equiv.).After 16 h, LC-MS analysis shows full conversion to expected product.The mixture is combined with H₂O (100 mL) and EtOAc (100 mL) in aseparatory funnel and agitated. The aqueous phase is collected, madebasic by the addition of NaOH (5.2 g, 130 mmol, 210 equiv.) andextracted with DCM (100 mL). The organic phase is collected, washed withbrine (100 mL) and dried over MgSO₄. After filtration, volatiles areremoved from the filtrate via rotary evaporation to give a pale yellowoil. LCMS: MW (calcd): 243; m/z MW (obsd): 244-246 (M+H).

1.1.3.1.3 Method A4c (with HCl in Dioxane+Basic Work-Up)

To a solution of N-tert-butoxycarbonyl derivative (1 eq.) inacetonitrile or DCM is added HCl 4N in dioxane (10 to 40 eq.). Thereaction mixture is stirred at r.t. for 1 h to 2 days, concentrated invacuo and the residue is taken up in water and EtOAc or DCM. The aqueouslayer is separated and basified with NaOH 1N solution or with asaturated Na₂CO₃ or NaHCO₃ solution and extracted with EtOAc or DCM. Thecombined organic layers are dried over anhydrous Na₂SO₄ (or MgSO₄),filtered and concentrated in vacuo to afford the expectedarylpiperidine.

Illustrative Synthesis of Int 38

To 4-(4-Fluoro-5-methoxy-2-methyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (450 mg, 1.39 mmol, 1.0 eq.) is added 4M HCl in1,4-dioxane (6 ml) and the mixture is stirred at room temperature. After3 h, conversion is complete. The reaction mixture is diluted with water,a solution of NaHCO₃ is added and the compound is extracted with DCM.Organic layers are combined and evaporated under reduced pressure toobtain expected compound.

LCMS: MW (calcd): 223; m/z MW (obsd): 224 (M+H).

1.1.3.2. Method A5: Synthesis of Substituted Piperidine—IllustrativeSynthesis (Int 36 & Int 37)

Step i)

To a solution of 3,4-difluorophenyl boronic acid (2.295 g, 14.53 mmol, 1eq.) in DME/water (75/75 mL) under argon at r.t. are added4-bromo-methylpyridine hydrochloride (2.5 g. 12.06 mmol, 1 eq.) andNaHCO₃ (4.8 g, 58.13 mmol, 4 eq.). The reaction mixture is purged withargon and Pd(PPh3)4 (1.7 g, 1.453 mmol, 0.1 eq.) is added. Reactionmixture is heated at 100° C. overnight, filtered through a pad ofcelite, diluted with EtOAc and washed with water and brine. The organicphase is dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. Purification by flash chromatography on silica gel affords theexpected aryl pyridine derivative. LCMS: MW (calcd): 205; m/z MW (obsd):207 (M+H).

Step ii)

To a solution of 4-(3,4-difluoro-phenyl)-3-methyl-pyridine hydrochloride(2 g, 9.74 mmol, 1 eq.) in ethanol (40 mL), is added platinum(IV) oxide(450 mg, 1.98 mmol, 0.2 eq.), and the reaction mixture is hydrogenatedin Parr apparatus at 30 psi and r.t. for 4.5 h. The reaction mixture isfiltered, washed with ethanol and the filtrate is concentrated in vacuoto afford 4-(3,4-difluorophenyl)-3-methyl-piperidine as a mixture ofdiastereoisomers. LCMS: MW (calcd): 211; in 2 peaks, m/z MW (obsd): 212(M+H).

Step iii)

1 g of the mixture of diastereoisomers is purified by preparativechromatography (12 runs×80 mg/1 mL). First two fractions of each run arecombined and solvent concentrated in vacuo to afford Int36. LCMS: MW(calcd): 211; m/z MW (obsd): 212 (M+H).

1.1.4. General Methods B: Preparation of Ketoester 1.1.4.1. Method B1:From Meldrum's Acid

Step i)

To a solution of the carboxylic acid (1 eq.) in DCM at 0° C. under N2atmosphere is added portionwise DMAP (1.5 eq.) then2,2-Dimethyl-[1,3]dioxane-4,6-dione (1.1 eq.) then EDC.HCl (1.2 eq.).After 10 min at 0° C., the reaction mixture is warmed to r.t. andstirred for 4 h. The reaction mixture is quenched with a solution ofKHSO₄ 5%. The aqueous phase is extracted with DCM, the combined organiclayers are washed with a solution of KHSO₄ 5%., water and brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. This residueis taken up in anhydrous toluene and benzyl alcohol (1.1 eq.) is added.The reaction mixture is stirred at 120° C. for 16 h to 20 h,concentrated in vacuo and purified by flash chromatography on silica gelto afford the expected γ-ketoester.

Step ii)

To a solution of the γ-ketoester (1 eq.) in MEK are added K₂CO₃ (2 eq.),NaI (0.1 eq.) and bromo derivative (1 eq.). The reaction mixture isstirred at 90° C. for 6 h to 16 h and cooled to room temperature. Wateris added, reaction mixture acidified to pH 8 and extracted with EtOAc.The combined organic layers are washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel to afford the expectedγ-ketoester.

Step iii)

To a solution of the γ-ketoester (1 eq.) in MeOH are added Pd(OH)₂/C(0.01 eq.), and cyclohexene (50 eq.). The reaction mixture is stirred at70° C. for 19 h. The reaction mixture is filtered on celpure P65 and thefiltrate is concentrated in vacuo. The residue is purified by flashchromatography on silica gel to afford the expected γ-ketoester.

Illustrative Synthesis of tert-butyl 5-methoxy-2-methyl-4-oxo-pentanoate(Precursor of Int 9)

Step i)

To a solution of methoxy-acetic acid (5.11 mL, 0.067 mol, 1 eq.) in DCM(160 mL) at 0° C. under N₂ atmosphere is added portionwise DMAP (12.21g, 0.100 mol, 1.5 eq.) then 2,2-Dimethyl-[1,3]dioxane-4,6-dione (10.56g, 0.073 mol, 1.1 eq.) then EDC.HCl (15.32 g, 0.080 mol, 1.2 eq.). After10 min at 0° C., the reaction mixture is warmed to r.t. and stirred for4 h. The reaction mixture is quenched with a solution of KHSO₄ 5%. Theaqueous phase is extracted with DCM, the combined organic layers arewashed with a solution of KHSO₄ 5%, water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. This residue istaken up in anhydrous toluene (220 mL) and benzyl alcohol (7.59 mL,0.073 mol, 1.1 eq.) is added. The reaction mixture is stirred at 120° C.for 16 h, concentrated in vacuo and purified by flash chromatography onsilica gel (eluting with DCM 100%) to afford the expected γ-ketoester.LCMS: MW (calcd): 222; m/z MW (obsd): 245.3 (M+Na)

Step ii)

To a solution of the γ-ketoester (8.96 g, 0.040 mol, 1 eq.) in MEK (120mL) are added K₂CO₃ (11.14 g, 0.081 mol, 2 eq.), NaI (0.6 g, 0.004 mol,0.1 eq.) and 2-Bromo-propionic acid tert-butyl ester (6.69 mL, 0.040mol, 1 eq.). The reaction mixture is stirred at 90° C. for 6 h andcooled to r.t. Water is added, and the reaction mixture is acidified topH 8 and extracted with EtOAc. The combined organic layers are washedwith water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel (eluting with Heptane/EtOAc 100/0 to 50/50) to afford theexpected γ-ketoester. LCMS: MW (calcd): 350; m/z MW (obsd): 373.4 (M+Na)

Step iii)

To a solution of the γ-ketoester (6.42 g, 0.018 mol, 1 eq.) in MeOH areadded Pd(OH)₂/C (0.642 g, 0.002 mol, 0.01 eq.), and cyclohexene (93 mL,0.916 mol, 50 eq.). The reaction mixture is stirred at 70° C. for 19 h.The reaction mixture is filtered on celpure P65, washed with MeOH andthe filtrate is concentrated in vacuo. The residue is purified by flashchromatography on silica gel (eluting with Heptane/EtOAc 100/0 to 70/30)to afford the expected product. LCMS: MW (calcd): 216; m/z MW (obsd):239.3 (M+Na).

1.1.4.2. Method B2: With Teat-Butyl Bromoacetate Illustrative Synthesisof tert-butyl 4-cyclopropyl-4-oxo-butanoate (Precursor of Int 2)

A solution of LDA (3.0 L, 5.98 mol, 1.17 eq.) in THF (2.5 L) is cooledto −78° C. A solution of 1-cyclopropylethanone (460 g, 5.11 mol, 1 eq.)in THF (0.5 L) is added dropwise, then warmed to 20° C. and stirred for30 min. The reaction mixture is cooled to −78° C. and tert-butylbromoacetate (997 g, 5.11 mol, 1 eq.) in THF (0.5 L) is added slowly.The reaction is stirred at 0° C. overnight, quenched with saturatedNH₄Cl aq. (3.3 L), extracted with EtOAc (0.5 L×3), washed with water(0.5 L×2), saturated NH₄Cl aq. (1 L), and brine (1 L), dried overanhydrous Na₂SO₄. Purification by distillation under reduced pressure (5mbar, 95° C.) affords the expected γ-ketoester.

1.1.4.3. Method B3: Stetter Reaction

A vial is charged with aldehyde (1 eq.), tert-butyl ester acrylate (1eq.), PBu3 (1 eq.) and dry THF. The vial is capped and heated at 70° C.for 2 h to 16 h. The reaction mixture is partitioned between EtOAc andwater. The combined organic layers are washed with brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to afford theexpected γ-ketoester after purification by flash chromatography onsilica gel.

Illustrative Synthesis of tert-butyl 4-oxo-4-(3-pyridyl)butanoate(Precursor of Int 1)

A vial is charged with pyridine-3-carboxaldehyde (16 mL, 170 mmol, 1eq.), tert-butyl ester acrylate (24.8 mL, 170 mmol, 1 eq.), PBu3 (42.5mL, 170 mmol, 1 eq.) and dry THF (300 mL). The vial is capped and heatedat 70° C. for 16 h. The reaction mixture is partitioned between EtOAcand water. The combined organic layers are washed with saturated NH₄Cl,dried over anhydrous MgSO₄, filtered and concentrated in vacuo to affordcrude expected compound that is then purified by flash chromatography onsilica gel. LCMS: MW (calcd): 235; m/z MW (obsd): 236 (M+H).

1.2. General Method C: Preparation of Ketoacids

Step i)

A round bottomed flask is charged with imidazole (2.0 eq.) and DCM. Upondissolution, acyl chloride (1.0 eq) is added. After 16 h, the mixture isfiltered. Volatiles are removed from the filtrate via rotaryevaporation. The residue is combined with DCM and Meldrum's acid(2,2-Dimethyl-1,3-dioxane-4,6-dione)(1.0 eq.) in a flask, sealed with anoil bubbler. After 16 h, complete conversion is observed. The mixture iscombined with H₂O and concentrated aqueous HCl (37%, 1.5 equiv.) in aseparatory funnel and agitated. The organic phase is collected, washedwith brine and dried over MgSO₄. After filtration, volatiles are removedfrom the filtrate via rotary evaporation. This residue is taken up inethanol and stirred at reflux overnight, concentrated in vacuo andpurified by flash chromatography on silica gel or distillation undervacuum to afford the expected beta-ketoester.

Step ii)

To a solution of beta-ketoester (1 eq.) in MEK (concentration-0.5 M) areadded K₂CO₃ (2 eq.), NaI (0.1 eq.) and 2-Bromo-propionic acid tert-butylester (1.0 to 1.05 eq.). The reaction mixture is heated at reflux for 40to 64 h and cooled to room temperature. Water is added, and the reactionmixture is acidified to pH 8 and extracted with EtOAc. The combinedorganic layers are washed with water and brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to afford the expectedγ-ketoester used as such in the next step.

Step iii)

To a solution of the γ-ketoester (1 eq.) in EtOH (concentration-0.1 M)is added a solution of NaOH (3 eq.) in water (1:1 volume with ethanol).The reaction mixture is heated at reflux for 16 h, cooled to r.t.,diluted with water and cooled in an ice bath. To this is added dropwiseH₃PO₄ (85%, 0.2 to 0.6 eq) and conc. HCl (2.5 to 2.8 eq.), the ice bathis removed and reaction mixture is stirred at room temperature for 30min. The reaction mixture is cooled in an ice bath and a solution ofNaOH (solid or aqueous solution, 3 eq.) is added to adjust the pH to 8to 10. The solution is combined with DCM or CHCl₃, the aqueous layer iscollected, cooled in an ice bath and the pH adjusted to pH=2 with conc.HCl. The solution is saturated with NaCl and extracted with DCM orCHCl₃. The combined organic layers are then dried over anhydrous MgSO₄,filtered, concentrated in vacuo to afford the expected product, which isthen either distilled, or used as such.

Illustrative Synthesis of Int 11

Step i)

A round bottomed flask (2 L) is charged with imidazole (109 g, 1.6 mol,2.0 eq.) and DCM (750 mL). Upon dissolution, methoxyacetyl chloride(73.0 mL, 0.80 mol, 1.0 eq) is added. After 16 h, the mixture isfiltered. Volatiles are removed from the filtrate via rotary evaporationto give a light brown oil.

The liquid residue is then combined with DCM (500 mL) and Meldrum's acid(2,2-Dimethyl-1,3-dioxane-4,6-dione) (115 g, 0.80 mol, 1.0 eq.) in around bottomed flask (1 L) sealed with an oil bubbler. After 16 h, LCMSanalysis shows complete conversion. The mixture is combined with H₂O(1.2 L) and concentrated aqueous HCl (37%, 100 mL, 1.20 mol, 1.5 equiv.)in a separatory funnel and agitated. The organic phase is collected,washed with brine (1 L) and dried over MgSO₄. After filtration,volatiles are removed from the filtrate via rotary evaporation. Theresidue (143.31 g) is combined with ethanol (400 mL) in a round bottomedflask (1 L) equipped with a reflux condensor and sealed with an oilbubbler and heated to reflux. After 16 h, the flask is allowed to coolto room temperature. Volatiles are removed via rotary evaporation, andthe residue is distilled under vacuum (120° C. at 0.5 mbar) to give acolorless liquid.

Step ii)

A three necked, round bottomed flask (2 L) is charged withbeta-ketoester (95.9 g, 0.60 mol), tert-butyl bromopropionate (102 mL,0.610 mol, 1.02 eq.), NaI (9.15 g, 61.0 mmol, 0.10 eq.), K₂CO₃ (165.63g, 1.2 mol, 2.0 eq.) and MEK (1 L). The flask is equipped with amechanical agitator and reflux condensor, sealed with an oil bubbler andheated to reflux. After 64 h, the mixture is allowed to cool to roomtemperature. Water (750 mL) is added, and when all solids are dissolved,the biphasic mixture is agitated in a separatory funnel. The organicphase is collected, washed with H₂O (750 mL) and brine (750 mL) anddried over MgSO₄. After filtration, volatiles are removed from thefiltrate via rotary evaporation to give the expected compound.

Step iii)

A round bottomed flask (3 L) is charged with ketodiester (145.93 g,0.506 mol), NaOH (61.26 g, 1.5 mol, 3.0 eq.), H₂O (500 mL) and EtOH (500mL). The flask is equipped with a mechanical agitator and refluxcondensor, sealed with an oil bubbler and heated to reflux. After 16 h,the mixture is allowed to cool to room temperature, diluted with H₂O(500 mL) and cooled in an ice bath. To this is added H₃PO₄ (85%, 7.0 mL,0.10 mol) followed by slow addition of HCl (aq) (37%, 110 mL, 1.32 mol,caution: vigorous effervescence) from and addition funnel, and then theice bath is removed. After 30 min, the flask is cooled in an ice bath,and NaOH (60.03 g, 1.501 mol) is added (caution: exothermic) to adjustthe pH to 10. To the resulting mixture is added H₂O (1.5 L) to dissolveall solids and render a homogeneous solution. The solution is washedwith CHCl₃ (500 mL), cooled in an ice bath, and then the pH is adjustedto pH=2, by addition of HCl(aq) (37%, 126 mL, 1.51 mol). The solution issaturated with NaCl and extracted with CHCl₃ (2×500 mL). The organicphases are pooled and dried over MgSO₄. After filtration, volatiles areremoved from the filtrate via rotary evaporation. The residue ispurified by vacuum distillation (200° C. at 0.2 mbar) to collect a paleyellow liquid.

1.3. General Method D: Bucherer Bergs Reaction

A pressure reactor or an open round bottom flask equipped with acondenser is charged with a solution of (NH₄)₂CO₃ or (NH₄)HCO₃ (8-12eq.) in water. KCN (2 to 4 eq.) is added portionwise then a solution ofγ-ketoester or γ-ketoamide (1 eq.) in EtOH is added. The vessel issealed and heated at 60-90° C. for 1 h to 2 days. The reaction mixtureis cooled to r.t., combined with water and extracted with AcOEt orCHCl₃/nBuOH 10%. The combined organic layers are washed with water andbrine, dried (over anhydrous Na₂SO₄ or MgSO₄), filtered and concentratedin vacuo. The residue is either recrystallized or purified by flashchromatography on silica gel to afford the expected hydantoinderivative.

Illustrative Synthesis trans tert-butyl2-methyl-3-(4-methyl-2,5-dioxo-imidazolidin-4-yl)propanoate (Precursorof Int 5)

A pressure reactor is charged with a solution of (NH₄)₂CO₃ (79.4 g,0.826 mol, 8 eq.) in water (400 mL). KCN (20 g, 0.307 mol, 3 eq.) isadded portionwise then a solution of γ-ketoester (19.15 g, 0.103 mol, 1eq.) in EtOH (400 mL) is added. The vessel is sealed and heated at 90°C. overnight. The reaction mixture is cooled to r.t., combined withwater and extracted with CHCl₃/nBuOH 10%. The combined organic layersare washed with brine, dried over anhydrous MgSO₄, filtered,concentrated in vacuo.

The above reaction is performed twice and the two crude residues aregathered for recrystallization. A flask is charged with the two cruderesidues, EtOH (250 mL) is added and the reaction mixture is heated atreflux. Upon complete dissolution, the reaction mixture is allowed tocool to r.t. for 2 days, it is then filtered and the crystalline solidis combined with EtOH (200 mL), heated to reflux, cooled to r.t.overnight and filtered to afford the expected hydantoin as a trans-Meracemic mixture (LCMS: >99% de, MW (calcd): 256; m/z MW (obsd): 257(M+H)).

1.4. General Method E: Method for Preparation of Hydantoin PropionicAcids

A flask is charged with tert-butyl ester (1 eq.) and HCl 4N in dioxane(5 to 40 eq.). In some cases, an additional solvent such as DCM, dioxaneor water is added to increase solubility. The reaction mixture isstirred at r.t. for 1 h to 4 days until complete conversion. Thereaction mixture is either concentrated in vacuo or filtered and washedwith Et₂O to afford the expected carboxylic acid.

Illustrative Synthesis of Int 2

A flask is charged with a solution of hydantoin (200 g, 746 mmol, 1.0eq.) in dioxane (100 mL) and is cooled in an ice bath, HCl 4N in dioxane(1 L) is added slowly. The reaction mixture is stirred at r.t. for 4 hand concentrated in vacuo. The resulting solid is suspended in 240 mL ofacetonitrile, then stirred at reflux for 1 h, and allowed to cool downto r.t. under stirring. The resulting solid is separated by filtration,washed twice with acetonitrile (2×30 mL), and finally dried under vacuumat 45° C. to afford the expected carboxylic acid. LC/MS: MW (calcd):212; m/z MW (obsd): 211 (M−H).

1.5. General Method F: Amide Bond Formation

1.5.1. Method F1: EDC/HOBt

A solution of acid (1 eq.), Et₃N (3 to 4 eq.), HOBt (0.1 to 1.1 eq.) inDMF (or DCM) is stirred at r.t. EDC.HCl (1 to 1.2 eq.) is added, thenamine (0.95 to 2 eq.) is added and the reaction mixture is stirred atr.t. for 5 h to 2 days. The reaction mixture is partitioned between DCM(or EtOAC) and water, extracted with DCM (or EtOAc). The combinedorganic layers are washed with water and brine, dried over anhydrousNa₂SO₄ (or MgSO₄), filtered, concentrated in vacuo and purified by flashchromatography on silica gel or preparative LCMS to afford the expectedamide.

Illustrative Synthesis of Cpd 3

A solution of 3-(4-Phenyl-2,5-dioxo-imidazolidin-4-yl)propionic acid (30mg, 0.12 mmol, 1 eq.), TEA (51 μL, 0.35 mmol, 3 eq.) and HOBT (18 mg,0.13 mmol, 1.1 eq) in DMF is stirred at room temperature for 5 min.EDC-HCl (28 mg, 0.15 mmol, 1.2 eq) is then added and the mixture isstirred at room temperature for 15 min. 4-phenylpiperidine in solutionin minimum amount of DMF is then added, and the reaction mixture isstirred at room temperature overnight. Solvent are evaporated underreduced pressure, and crude compound is then purified by LC/MSpreparative purification, to afford expected Cpd 3. LCMS: MW (calcd):391; m/z MW (obsd): 392 (M+H).

1.5.2. Method F2: HATU

A flask is charged with acid (1 eq.), amine (0.85 to 1.1 eq.), HATU(0.85 to 1.1 eq.) and DMF (or THF). DIPEA (2 to 6 eq.) is added and thereaction mixture is stirred at r.t. for 5 h to 2 days. The reactionmixture is partitioned between EtOAc and water, extracted with EtOAc.The combined organic layers are washed with water and brine, dried (overanhydrous Na₂SO₄, MgSO₄, or hydrophobic column), filtered, concentratedin vacuo and purified by flash chromatography on silica gel orpreparative LCMS to afford the expected amide.

Illustrative Synthesis of Cpd 84

Int 6 (12.0 g, 64.2 mmol, 1.2 eq.), Int 24 (15.0 g, 53.5 mmol, 1.0 eq),and HATU (22.4 g, 59.0 mmol, 1.1 eq) are stirred in DMF (350 mL). DIPEA(37 mL, 214 mmol, 4.0 eq) is then added. The mixture is then stirred atroom temperature for 1 h. The mixture is then concentrated under reducedpressure until a volume ˜50 mL, and the crude is partitioned betweenethyl acetate and water+brine. The aqueous layer is extracted with ethylacetate (3 times), and the combined organic layers are washed with bigamount of water (˜2 L), saturated NaHCO₃, then water again and finallybrine. The organic layer is then dried over Na₂SO₄, filtered andconcentrated to afford crude compound as a slightly pink solid.

The compound is then stirred in refluxing ethanol (280 mL) untildissolution of all the solid, and filtered. The solution is then let tocool back to room temperature, in a round bottom flask open to the air.After formation of small crystals, the mixture is sonicated untilcomplete crystallization of the compound. The solid obtained is thenfiltered and washed with cold ethanol to afford the expected compound.

The filtrate is concentrated under reduced pressure, until volume ofethanol ˜150 mL. Application of the same crystallization process cangive a new batch of expected compound. LCMS: MW (calcd): 411; m/z MW(obsd): 412 (M+H). Melting point of the two batches: 196-198° C.

1.5.3. Method F3: BOP

A flask is charged with acid (1 eq.), DMF (or DCM), DIPEA or Et₃N (2 to6 eq.) and BOP (0.77 to 1.1 eq.). After 5-15 min, amine (0.77 to 1.5eq.) is added and the reaction mixture is stirred at r.t. for 5 h to 2days. The reaction mixture is partitioned between EtOAc (or DCM) andwater, extracted with EtOAc (or DCM). The combined organic layers arewashed with water and brine, dried (over anhydrous Na₂SO₄, MgSO₄, orhydrophobic column), filtered, concentrated in vacuo and purified byflash chromatography on silica gel or preparative LCMS to afford theexpected amide.

Illustrative Synthesis of Cpd 20

A vial is charged with Int 3 (0.050 g, 0.221 mmol), DCM (2 mL), BOP(0.102 g, 0.231 mmol, 1.04 equiv.) and DIPEA (0.035 mL, 0.21 mmol, 0.97equiv.). After 5 min, 4-phenylpiperidine (0.044 g, 0.273 mmol, 1.23equiv.) and DIPEA (0.097 mL, 0.57 mmol, 2.6 equiv.) are added. After 16h, the mixture is combined with DCM (50 mL) and H₂O (50 mL) in aseparatory funnel and agitated. The organic phase is collected andwashed with brine (50 mL) and dried over MgSO₄. After filtration,volatiles are removed from the filtrate via rotary evaporation. Theresidue is purified by preparative HPLC. LCMS: MW (calcd): 369; m/z MW(obsd): 370 (M+H).

1.5.4. Method F4: Mukaiyama Reagent—Illustrative Synthesis of Cpd 1

A flask is charged with 3-[(4S)-2,5-dioxo-imidazolidin-4-yl]propionicacid (54 mg, 0.31 mmol, 1 eq.), 4-phenylpiperidine (76 mg, 0.47 mmol,1.5 eq.) and DMF (4 mL)+DCM (1 mL). Et₃N (169 μL, 1.25 mmol, 4 eq.) andPS-Mukaiyama reagent (load 1.17 mmol/g, 540 mg, 0.63 mmol, 2 eq.) areadded and the reaction mixture is stirred at r.t. for 18 h. Reactionmixture is filtered, washed with DCM and the filtrate is concentrated invacuo and purified by preparative LCMS to afford the expected Cpd 1.LCMS: MW (calcd): 315; m/z MW (obsd): 316 (M+H).

Example 2. Intermediate Synthesis 2.1. Synthesis of Int 4

A round bottomed flask (1 L) is charged with D-glutamic acid, H₂O andKOCN and heated at 80° C. After 6 h, the flask is allowed to cool toroom temperature. Aqueous HCl (6 N, 200 mL, 1.2 mol) is slowly added(caution: vigorous effervescence). The flask is then heated at 60° C.After 1 h, the flask is allowed to cool to room temperature. After 24 h,volatiles are removed via rotary evaporation. The resulting solid isstirred in 360 mL of boiling dioxane. The suspension is then hotfiltered, and the filtrate is let at room temperature over the weekend.

Evaporation of the filtrate gives a white crude product (15.7 g) that isrecrystallized from 140 mL of boiling water. New batch of expectedcompound is obtained (7.36 g), and the filtrate is concentrated (until˜20 mL of water), and cooled in the fridge for 3 h. The solid obtainedis then filtered, and washed with cold water, to give another batch ofclean expected compound (1.98 g). LCMS: MW (calcd): 172; m/z MW (obsd):171 (M−H).

2.2. Synthesis of Int 6

The racemic 3-(4-Methyl-2,5-dioxo-imidazolidin-4-yl)propionic acid (805g) is separated by SFC to afford 384 g of the faster eluting isomer and388 g of the slower eluting isomer. Conditions of the separation:Instrument: Thar350 preparative SFC, Column: ChiralPak AD-10 μm, 300×50mmI.D., Mobile phase: A for CO₂ and B for IPA (0.1% TFA), Gradient: B25%, Flow rate: 220 mL/min, Back pressure: 100 bar, Column temperature:38° C., Wavelength: 210 nm, Cycletime: ˜3.8 min, Sample preparation:Compound is dissolved in methanol to ˜80 mg/mL, Injection: 1.0 mL perinjection, Work up: After separation, the fractions are dried off viarotary evaporator at bath temperature 40° C. to get the desired isomers.

2.3. Synthesis of Int 7 (Chiral Separation)

The racemic hydantoin propionic acid is separated by SFC to afford afast eluting isomer ((R)-enantiomer) and a slow eluting isomer((S)-enantiomer).

The purification is done in 2 stages.

Conditions of the first separation: preparative SFC, Column: ChiralPakAD-10 μm, 300×50 mmI.D., Mobile phase: A for CO₂ and B for Ethanol,Gradient: B 45%, Flow rate: 200 mL/min, Back pressure: 100 bar, Columntemperature: 38° C., Wavelength: 220 nm, Cycletime: ˜10.0 min. Thecompound is dissolved in methanol to ˜120 mg/mL, and loaded on thecolumn (16 mL per injection). After separation, the fractions are driedoff via rotary evaporator to get the desired isomers.

Conditions of the second separation: Prep HPLC, Column: C18, 250×50 mmI.D., Mobile phase: A for H₂O and B for Acetonitrile, Gradient: B 5%-20%in 15 min linearly, Flow rate: 80 mL/min, Wavelength: 220 nm. Thecompound is dissolved in methanol (˜100 mg/mL) and loaded on the column(10 mL per injection). After separation, the fraction is concentratedvia rotary evaporator and the remaining aqueous layer is lyophilized.

2.4. Synthesis of Int 124

A solution of 1-bromo-4-chloro-3,5-difluorobenzene (100 mg, 0.44 mmol,1.0 eq.) and sodium methylate (59 mg, 1.1 mmol, 2.5 eq.) in DMA (0.6 mL)is heated at 100° C. for 3 h. Sodium methoxide (12 mg, 0.22 mmol, 0.5eq.) is added and the mixture is heated at 100° C. for 1 h, then cooledto r.t. Water (6 mL) is added and the solid is collected by filtrationand dried under suction to give the expected product.

2.5. Synthesis of Int 125

1-Bromo-4-chloro-2-fluoro-5-methyl-benzene (1.0 g, 4.5 mmol, 1.0 eq.) isdissolved in MeOH (10 mL) and a solution of sodium methoxide in MeOH(25% wt, 1.9 mL, 9.0 mmol, 2.0 eq.) is added. The reaction mixture issubmitted to microwave irradiation for 50 min at 120° C. The reactionmixture is diluted with water and extracted with DCM. The combinedorganic layers are dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. Crystallization upon standing and filtrationafford the expected product.

2.6. Synthesis of Int 126

A mixture of 3-chloro-4-fluoroanisole (2.52 g, 15.7 mmol, 1.0 eq.),silver trifluoroacetate (8.53 g, 38.6 mmol, 2.5 eq.), iodine (7.94 g,31.3 mmol, 2.0 eq.) and chloroform (100 mL) is stirred at r.t. for 16 h.The reaction mixture is filtered through a silica plug on a frittedfunnel and rinsed with chloroform. The filtrate is washed successivelywith an aqueous solution of Na₂S₂O₃, water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue is purified by flashchromatography on silica gel to afford the expected product.

2.7. Synthesis of Int 127

A mixture of 4-chloro-3-fluoroanisole (2.52 g, 15.7 mmol, 1.0 eq.),silver trifluoroacetate (8.57 g, 38.8 mmol, 2.5 eq.), iodine (7.95 g,31.3 mmol, 2.0 eq.) and chloroform (100 mL) is stirred at r.t. for 16 h.The reaction mixture is filtered through a silica plug on a frittedfunnel and rinsed with chloroform. The filtrate is washed successivelywith an aqueous solution of Na₂S₂O₃, water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue is purified by flashchromatography on silica gel to afford the expected product.

2.8. Synthesis of Int 128

1-bromo-3,4-dichloro-5-fluorobenzene (365 mg, 1.5 mmol, 1.0 eq.) isheated in a 0.5M solution of sodium methoxide in methanol (6.0 mL, 3.0mmol, 2.0 eq.) at 70° C. for 4 h, then at 85° C. for 18 h. The reactionmixture is cooled in an ice water bath. The solid is filtered and driedunder suction to afford the expected product.

2.9. Synthesis of Int 129

5-Bromo-3-chloro-2-fluorophenol (113 mg, 0.5 mmol, 1.0 eq.) is dissolvedin MeCN (1 mL) in a microwave vial. Iodomethane (94 μL, 1.5 mmol, 3.0eq.) and potassium carbonate (138 mg, 1.0 mmol, 2.0 eq.) aresuccessively added. The vial is submitted to microwave irradiation at100° C. for 10 min. The mixture is filtered and the salts are washedwith EtOAc. The filtrate is then partitioned between water and EtOAc.The organic phase is dried over Na₂SO₄, filtered and concentrated invacuo to afford the expected product, which is used as such in the nextstep.

2.10. Synthesis of Int 130

A solution of 1-bromo-4-chloro-3-fluoro-5-methoxy-benzene (542 mg, 2.3mmol, 1.0 eq.) and sodium ethoxide (308 mg, 4.6 mmol, 2.0 eq.) in DMA(2.3 mL) is heated at 110° C. for 1.5 h. The reaction mixture is thenpoured into 100 mL of water. The aqueous layer is extracted 3 times withEtOAc. The combined organic phases are washed successively with waterand brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the expected product which is used as such in the nextstep.

2.11. Synthesis of Int 131

Step i)

N-boc-2-methoxy aniline (2.0 g, 9.0 mmol, 1.0 eq) is stirred in dry Et₂Oat −78° C. t-BuLi in pentane (1.6 M, 17 mL, 27 mmol, 3.0 eq) is thenadded dropwise at −78° C. Once addition is complete, the mixture isstirred at −78° C. for 10 min, then 20 min at 0° C. The mixture is thencooled back to −78° C., and a solution of iodoethane (1.4 mL, 18.0 mmol,2.0 eq) in dry Et₂O is then added dropwise, and stirring is kept at −78°C. After a few min, the dry ice/acetone bath is removed, and the mixtureis warm up to room temperature and left at r.t. overnight. The mixtureis then carefully quenched with water. Brine is added, and the aqueouslayer is extracted with Et₂O (three times). The combined organic layersare dried over Na₂SO₄, and concentrated under reduced pressure and theresidue is purified by flash chromatography (Heptane/AcOEt 100/0 to85/15), to afford the expected compound. LCMS: MW (calcd): 251; m/z MW(obsd): 252 (M+H).

Step ii)

N-boc-substituted aniline (945 mg, 3.76 mmol, 1.0 eq) is stirred indioxane (5 mL), and HCl (4N in dioxane) is added. The mixture is stirredat r.t. for 1 h30, and water and EtOAc is added. NaOH (2M) is added tothe aqueous layer until a pH higher than 10 is reached, and is thenextracted with DCM (3 times). The combined organic layers are washedwith water, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford the expected deprotected aniline.

Step iii) and Step iv)

Identical procedures from synthesis of Int 132 Step i) and step ii) wereapplied for step iii) and step iv), to afford Int 131.

2.12. Synthesis of Int 132

Step i)

To a solution of 2-methoxy-6-methylaniline (13.47 g, 98.3 mmol, 1.0 eq.)in DCM (1.3 L) and MeOH (520 mL) is added benzyltrimethylammoniumtribromide (38.3 g, 98.3 mmol, 1.0 eq.) and calcium carbonate (39.3 g,393.2 mmol, 4.0 eq.). The reaction mixture is stirred at r.t. for 1 h.The solid is filtered and washed with DCM. The filtrate is washed twicewith water. The combined aqueous layers are extracted twice with Et₂O.The combined organic phases are dried over anhydrous Na₂SO₄, filtered,concentrated in vacuo to afford the expected product. LCMS: MW (calcd):215; m/z MW (obsd): 216-218 (M+H).

Step ii)

To 4-bromo-2-methoxy-6-methyl-aniline (20.85 g, 96.5 mmol, 1.0 eq.) in a6N aqueous HCl solution (54 mL, 326 mmol, 3.4 eq.) at 0° C. is addedslowly, under vigorous stirring, a 0° C.-cooled solution of sodiumnitrite (6.49 g, 94 mmol, 1.0 eq.) in water (27 mL). The resultingmixture is added quickly to a 0° C.-cooled solution of CuCl (46.1 g,465.5 mmol, 4.8 eq.) in concentrated HCl (41 mL), and the flask isrinsed with 75 mL of water. The reaction mixture is stirred at 0° C. for30 min, then at reflux for 18 h. The reaction mixture is cooled back tor.t., diluted with water and brine and extracted 3 times with DCM. Thecombined organic phases are washed successively with water and brine,dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo. Theresidue is stirred in 300 mL of heptane at 100° C. for 15 min, filteredand washed with heptane. The filtrate is concentrated under reducedpressure and the residue is purified by flash chromatography on silicagel to afford the expected product.

2.13. Synthesis of Int 133

Step i)

1-bromo-4-chloro-3,5-difluorobenzene (682 mg, 3.0 mmol, 1.0 eq.),dimethylamine hydrochloride (734 mg, 9.0 mmol, 3.0 eq.) and DIPEA (2.1mL, 12.0 mmol, 4.0 eq.) are heated in DMA (2.1 mL) in a sealed microwavevial at 125° C. for 18 h. The reaction mixture is then poured into waterand brine. The aqueous layer is extracted 3 times with EtOAc. Thecombined organic phases are washed successively with water and brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toafford the expected product. LCMS: MW (calcd): 251; m/z MW (obsd):252-254 (M+H).

Step ii)

A solution of (5-bromo-2-chloro-3-fluoro-phenyl)-dimethyl-amine (599 mg,2.4 mmol, 1.0 eq.) and sodium methoxide (259 mg, 4.8 mmol, 2.0 eq.) inDMA (2.4 mL) is heated at 110° C. for 2 h. The reaction mixture is thenpoured into 1000 mL of water and ice, stirred and extracted 3 times withEtOAc. The combined organic phases are washed successively with waterand brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the expected product. LCMS: MW (calcd): 263; m/z MW(obsd): 264-266 (M+H).

2.14. Synthesis of Int 134

A solution of 1-bromo-3,4-difluoro-5-methoxy-benzene (1.11 g, 5.0 mmol,1.0 eq.) and sodium methoxide (405 mg, 7.5 mmol, 1.5 eq.) in DMA (5 mL)is heated at 100° C. for 1 h. The reaction mixture is then poured into60 mL of water and ice, stirred and the resulting solid is filtered anddried under suction to afford the expected product.

TABLE II Illustrative intermediate for the synthesis of illustrativecompounds of the invention trans:

Int Structure Name Mtd SM MW Ms'd 1

3-[2,5-dioxo-4-(3- pyridyl) imidazolidin- 4- yl]propanoic acid E + D +B3 pyridine-3- carboxaldehyde + tert-butyl ester acrylate 249 N/A 2

3-(4-cyclopropyl- 2,5-dioxo- imidazolidin-4- yl)propanoic acid E + D +B2 1- cyclopropyl- ethanone + tert-butyl bromoacetate 212 211 (M − H) 3

3-(4-cyclopropyl- 2,5- dioxo- imidazolidin-4- yl)-2-methyl- propanoicacid E + D + B1 cyclopropane- carboxylic acid + 2,2-Dimethyl-[1,3]dioxane- 4,6-dione + 2- Bromo- propionic acid tert-butyl ester 226225 (M − H) 4

3-[(4R)-2,5- dioxo- imidazolidin-4- yl]propionic acid 2.1 D-Glutamicacid 172 171 (M − H) 5

2-methyl-3-(4- methyl-2,5-dioxo- imidazolidin-4- yl)propanoic acid E +D + B1 ii)-iii) benzyl 3- oxobutanoate + 2-Bromo- propionic acidtert-butyl ester 200 201 (M + H) 6

3-[(4R)-4-methyl- 2,5-dioxo- imidazolidin-4- yl]propanoic acid 2.23-(4-Methyl- 2,5-dioxo- imidazolidin-4- yl)propionic acid 186 373 (2M +H) 7

3-[(4S)-4- cyclopropyl-2,5- dioxo- imidazolidin-4- yl]propanoic acid 2.3Int 2 212 N/A 8

3-[4-(6-methyl-2- pyridyl)-2,5- dioxo- imidazolidin-4- yl]propanoic acidE + D + B3 6- methylpyridine- 2-carbaldehyde + tert-butyl ester acrylate263 264 (M + H) 9

3-[4- (methoxymethyl)- 2,5-dioxo- imidazolidin-4- yl]-2-methyl-propanoic acid E + D + B1 2-methoxyacetic acid + 2,2- Dimethyl-[1,3]dioxane- 4,6-dione + 2- Bromo-propionic acid tert-butyl ester 230231 (M + H) 10

2-methyl-4-oxo- pentanoic acid C ii)- iii) ethyl 3- oxobutanoate +2-Bromo- propionic acid tert-butyl ester 130 N/A 11

5-methoxy-2- methyl-4-oxo- pentanoic acid C methoxyacetyl chloride +2,2- Dimethyl-1,3- dioxane-4,6- dione + 2- Bromo- propionic acidtert-butyl ester 160 N/A 12

1-[4-(4-chloro-3- fluoro-5- methoxy-phenyl)- 1-piperidyl]-2-methyl-pentane- 1,4-dione F3 Int 10 + Int 24 355 356-358 (M + H) 13

1-[4-(4-chloro-3- fluoro-5- methoxy-phenyl)- 1-piperidyl]-5- methoxy-2-methyl-pentane- 1,4-dione F3 Int 11 + Int 24 385 386-388 (M + H) 14

1-cyclopropyl-4- (4-phenyl-1- piperidyl)butane- 1,4-dione F35-cyclopropyl- 4-oxo-hexanoic acid + 4- phenylpiperidine 285 286 (M + H)15

5-methyl-1-(4- phenyl-1- piperidyl)hexane- 1,4-dione F3 5-methyl-4-oxo-hexanoic acid + 4- phenylpiperidine 287 288 (M + H) 16

4-(4-chloro-3,5- dimethoxy- phenyl)piperidine A4a Int 55 255 256-258(M + H) 17

4-(4-chloro-3- methoxy- phenyl)piperidine A4a Int 56 225 226-228 (M + H)18

4-(4-chloro-5- methoxy-2- methyl- phenyl)piperidine A4a Int 57 239240-242 (M + H) 19

4-(3,5-dimethoxy- phenyl)piperidine A4a Int 58 221 222 (M + H) 20

4-(2,5-dimethoxy- phenyl)piperidine A4a Int 59 221 222 (M + H) 21

4-(5-chloro-2- methoxy- phenyl)piperidine A4a Int 60 225 226-228 (M + H)22

4-(4-chloro-2- methoxy- phenyl)piperidine A4a Int 61 225 226-228 (M + H)23

4-(3,4-difluoro-5- methoxy- phenyl)piperidine A4a Int 62 227 228 (M + H)24

4-(4-chloro-3- fluoro-5- methoxy- phenyl)piperidine A4a Int 63 243244-246 (M + H) 25

4-(3,5-dichloro-2- methyl- phenyl)piperidine A4a Int 64 244 244-246 (M +H) 26

4-(3-fluoro-5- methoxy- phenyl)piperidine A4a Int 65 209 210 (M + H) 27

4-(4-chloro-3- fluoro- phenyl)piperidine A4a Int 66 213 214-216 (M + H)28

4-(4-fluoro-3- methoxy- phenyl)piperidine A4a Int 67 209 210 (M + H) 29

4-(3,4-difluoro- phenyl)piperidine A4a Int 68 197 198 (M + H) 30

4-(4-chloro-2- methyl-phenyl)- piperidine A4a Int 69 209 N/A 31

4-(4,5-dichloro-2- methoxy-phenyl)- piperidine A4a Int 70 260 N/A 32

4-(4-chloro-5- fluoro-2-methyl- phenyl)- piperidine A4a Int 71 227 N/A33

4-(4,5-dichloro-2- methyl-phenyl)- piperidine A4a Int 72 244 N/A 34

4-(4-fluoro-3,5- dimethoxy- phenyl)piperidine A4a Int 73 239 240 (M + H)35

4-(3-chloro-4- fluoro-5- methoxy- phenyl)piperidine A4a Int 74 243 N/A36

(cis)-4-(3,4- difluorophenyl)- 3-methyl- piperidine A5 3,4-difluorophenyl boronic acid + 4-bromo- methylpyridine hydrochloride 211212 (M + H) 37

(trans)-4-(3,4- difluorophenyl)- 3-methyl- piperidine A5 3,4-difluorophenyl boronic acid + 4-bromo- methylpyridine hydrochloride 211N/A 38

4-(4-Fluoro-5- methoxy-2- methyl-phenyl)- piperidine A4c Int 75 223 224(M + H) 39

4-(3-chloro-2- methoxy- phenyl)piperidine A4a Int 76 225 392 (M + H) 40

4-(4-chloro-3- ethoxy-5- methoxy- phenyl)piperidine A4a Int 77 269270-272 (M + H) 41

4-(4-Chloro-2- methoxy-5- methyl-phenyl)- piperidine A4c Int 78 239240-242 (M + H) 42

2-chloro-3- methoxy-N,N- dimethyl-5-(4- piperidyl)aniline A4a Int 79 268269-271 (M + H) 43

4-(4,5-dichloro-2- methoxy- phenyl)piperidine A4a Int 80 260 N/A 44

4-(4-Chloro-3,5- dimethyl-phenyl)- piperidine A4c Int 81 223 224-226(M + H) 45

4-(4-Chloro-3- methyl-phenyl)- piperidine A4a Int 82 209 N/A 46

4-(4-chloro-3- methoxy-5- methyl- phenyl)piperidine A4a Int 83 239240-242 (M + H) 47

4-(4-chloro-5- fluoro-2- methoxy- phenyl)piperidine A4b Int 84 243244-246 (M + H) 48

4-(5-chloro-4- fluoro-2- methoxy- phenyl)piperidine A4b Int 85 243 246(M + H) 49

4-(4-chloro-3- ethyl-5-methoxy- phenyl)piperidine A4a Int 86 253 254-256(M + H) 50

4-[5-(2- fluorophenyl)-2- thienyl]piperidine A4a Int 87 261 N/A 51

4-(4-Chloro-3- trifluoromethyl- phenyl)- piperidine A4c Int 88 263364-366 (M + H) 52

4-(3,5-dichloro-2- methoxy- phenyl)piperidine A4a Int 89 260 N/A 53

4-(3-chloro-5- methoxy- phenyl)piperidine A4a Int 90 225 N/A 54

4-(3,4-dichloro-5- methoxy- phenyl)piperidine A4a Int 91 260 N/A 55

tert-butyl 4-(4- chloro-3,5- dimethoxy- phenyl)piperidine- 1-carboxylateA3 Int 124 + tert- butyl 4- iodopiperidine- 1-carboxylate 355 300-302(M + H- tBu) 56

tert-butyl 4-(4- chloro-3- methoxy- phenyl)piperidine- 1-carboxylate A2Int 92 325 270-272 (M + H- tBu) 57

tert-butyl 4-(4- chloro-5- methoxy-2- methyl- phenyl)piperidine-1-carboxylate A3 5-bromo-2- chloro-4- methylanisole + tert-butyl 4-iodopiperidine- 1-carboxylate 339 284-286 (M + H- tBu) 58

tert-butyl 4-(3,5- dimethoxyphenyl) piperidine-1- carboxylate A31-bromo-3,5- dimethoxybenzene + tert-butyl 4- iodopiperidine-1-carboxylate 321 266 (M + H- tBu) 59

tert-butyl 4-(2,5- dimethoxyphenyl) piperidine-1- carboxylate A31-bromo-2,5- dimethoxybenzene + tert-butyl 4- iodopiperidine-1-carboxylate 321 266 (M + H- tBu) 60

tert-butyl 4-(5- chloro-2- methoxy- phenyl)piperidine- 1-carboxylate A2Int 93 325 270-272 (M + H- tBu) 61

tert-butyl 4-(4- chloro-2- methoxy- phenyl)piperidine- 1-carboxylate A32-bromo-5- chloro-anisole + tert-butyl 4- iodopiperidine- 1-carboxylate325 270-272 (M + H- tBu) 62

tert-butyl 4-(3,4- difluoro-5- methoxy- phenyl)piperidine- 1-carboxylateA3 5-bromo-2,3- difluoro-anisole + tert-butyl 4- iodopiperidine-1-carboxylate 327 272 (M + H- tBu) 63

tert-butyl 4-(4- chloro-3-fluoro-5- methoxy- phenyl)piperidine-1-carboxylate A2 Int 94 343 288-290 (M + H- tBu) 64

tert-butyl 4-(3,5- dichloro-2- methyl- phenyl)piperidine- 1-carboxylateA2 Int 95 344 288-290 (M + H- tBu) 65

tert-butyl 4-(3- fluoro-5- methoxy- phenyl)piperidine- 1-carboxylate A2Int 96 309 254 (M + H- tBu) 66

tert-butyl 4-(4- chloro-3-fluoro- phenyl)piperidine- 1-carboxylate A2Int 97 313 258-260 (M + H- tBu) 67

tert-butyl 4-(4- fluoro-3- methoxy- phenyl)piperidine- 1-carboxylate A2Int 98 309 254 (M + H- tBu) 68

tert-butyl 4-(3,4- difluorophenyl) piperidine-1- carboxylate A2 Int 99297 242 (M + H- tBu) 69

tert-butyl 4-(4- chloro-2-methyl- phenyl)piperidine- 1-carboxylate A2Int 100 309 N/A 70

tert-butyl 4-(4,5- dichloro-2- methoxy- phenyl)piperidine- 1-carboxylateA2 Int 101 360 N/A 71

tert-butyl 4-(4- chloro-5-fluoro-2- methyl- phenyl)piperidine-1-carboxylate A2 Int 102 327 N/A 72

tert-butyl 4-(4,5- dichloro-2-methyl- phenyl)piperidine- 1-carboxylateA2 Int 103 344 N/A 73

tert-butyl 4-(4- fluoro-3,5- dimethoxy- phenyl)piperidine- 1-carboxylateA2 Int 104 339 284 (M + H- tBu) 74

tert-butyl 4-(3- chloro-4-fluoro-5- methoxy- phenyl)piperidine-1-carboxylate A2 Int 105 343 N/A 75

tert-butyl 4-(4- fluoro-5- methoxy-2- methyl- phenyl)piperidine-1-carboxylate A2 Int 106 323 266 (M + H- tBu) 76

tert-butyl 4-(3- chloro-2- methoxy- phenyl)piperidine- 1-carboxylate A2Int 107 325 270 (M + H- tBu) 77

tert-butyl 4-(4- chloro-3-ethoxy- 5-methoxy- phenyl)piperidine-1-carboxylate A2 Int 108 369 314-316 (M + H- tBu) 78

tert-butyl 4-(4- chloro-2- methoxy-5- methyl- phenyl)piperidine-1-carboxylate A2 Int 109 339 284-286 (M + H- tBu) 79

tert-butyl 4-[4- chloro-3- (dimethylamino)- 5-methoxy-phenyl]piperidine- 1-carboxylate A2 Int 110 368 369-371 (M + H- tBu) 80

tert-butyl 4-(4,5- dichloro-2- methoxy- phenyl)piperidine- 1-carboxylateA2 Int 111 360 N/A 81

tert-butyl 4-(4- chloro-3,5- dimethyl- phenyl)piperidine- 1-carboxylateA2 Int 112 323 268-270 (M + H- tBu) 82

tert-butyl 4-(4- chloro-3-methyl- phenyl)piperidine- 1-carboxylate A2Int 113 309 N/A 83

tert-butyl 4-(4- chloro-3- methoxy-5- methyl- phenyl)piperidine-1-carboxylate A2 Int 114 339 284-286 (M + H- tBu) 84

tert-butyl 4-(4- chloro-5-fluoro-2- methoxy- phenyl)piperidine-1-carboxylate A2 Int 115 343 288-290 (M + H- tBu) 85

tert-butyl 4-(5- chloro-4-fluoro-2- methoxy- phenyl)piperidine-1-carboxylate A2 Int 116 343 288-290 (M + H- tBu) 86

tert-butyl 4-(4- chloro-3-ethyl-5- methoxy- phenyl)piperidine-1-carboxylate A2 Int 117 353 298-300 (M + H- tBu) 87

tert-butyl 4-[5-(2- fluorophenyl)-2- thienyl]piperidine- 1-carboxylateA2 Int 118 361 306 (M + H- tBu) 88

tert-butyl 4-[4- chloro-3- (trifluoromethyl) phenyl]piperidine-1-carboxylate A2 Int 119 363 308-310 (M + H- tBu) 89

tert-butyl 4-(3,5- dichloro-2- methoxy- phenyl)piperidine- 1-carboxylateA2 Int 120 360 N/A 90

tert-butyl 4-(3- chloro-5- methoxy- phenyl)piperidine- 1-carboxylate A2Int 121 325 N/A 91

tert-butyl 4-(3,4- dichloro-5- methoxy- phenyl)piperidine- 1-carboxylateA2 Int 122 360 N/A 92

tert-butyl 4-(4- chloro-3- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 4-bromo-1- chloro-2 methoxyphenyl + tert-butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 323 298-230 (M + H- tBu) 93

tert-butyl 4-(5- chloro-2- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 2-bromo-4- chloroanisole + tert-butyl 4- (4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 323 268-270 (m + H- tBu) 94

tert-butyl 4-(4- chloro-3-fluoro-5- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 5-bromo-2- chloro-1-fluoro- 3-methoxy-benzene + tert- butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 341 286-288 (M + H- tBu) 95

tert-butyl 4-(3,5- dichloro-2- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 1-bromo-3,5- dichloro-2- methyl-benzene +tert-butyl 4- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 342 286-288 (M + H- tBu) 96

tert-butyl 4-(3- fluoro-5- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 1-bromo-3- fluoro-5- methoxy- benzene + tert- butyl4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 307 252 (M + H- tBu) 97

tert-butyl 4-(4- chloro-3-fluoro- phenyl)-3,6- dihydro-2H- pyridine-1-carboxylate A1 4-chloro-3- fluoro- bromobenzene + tert-butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 311 256-258 (M + H- tBu) 98

tert-butyl 4-(4- fluoro-3- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 5-bromo-2- fluoroanisole + tert-butyl 4- (4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 307 252-254 (m + H- tBu) 99

tert-butyl 4-(3,4- difluorophenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 1-bromo-3,4- difluorobenzene + tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 295 240 (M + H- tBu) 100

tert-butyl 4-(4- chloro-2-methyl- phenyl)-3,6- dihydro-2H- pyridine-1-carboxylate A1 2-bromo-5- chlorotoluene + tert-butyl 4- (4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 307 N/A 101

tert-butyl 4-(4,5- dichloro-2- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 2-bromo-4,5- dichloroanisole + tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 358 N/A 102

tert-butyl 4-(4- chloro-5-fluoro-2- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 2-bromo-5- chloro-4- fluorotoluene +tert-butyl 4- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 325 N/A 103

tert-butyl 4-(4,5- dichloro-2- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 2-bromo-4,5- dichlorotoluene + tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 342 N/A 104

tert-butyl 4-(4- fluoro-3,5- dimethoxy- phenyl)-3,6- dihydro-2H-pyridine-1- carboxylate A1 Int 134 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 337 282 (M + H- tBu) 105

tert-butyl 4-(3- chloro-4-fluoro-5- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 129 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 341 N/A 106

tert-butyl 4-(4- fluoro-5- methoxy-2- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 1-Bromo-4- fluoro-5- methoxy-2-methyl-benzene + tert-butyl 4- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 321 266 (M +H- tBu) 107

tert-butyl 4-(3- chloro-2- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 2-bromo-6- chloroanisole + tert-butyl 4- (4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 323 324 (M + H) 108

tert-butyl 4-(4- chloro-3-ethoxy- 5-methoxy- phenyl)-3,6- dihydro-2H-pyridine-1- carboxylate A1 Int 130 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 367 312-314 (M + H- tBu) 109

tert-butyl 4-(4- chloro-2- methoxy-5- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 125 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 337 282-284 (M + H- tBu) 110

tert-butyl 4-[4- chloro-3- (dimethylamino)- 5-methoxy- phenyl]-3,6-dihydro-2H- pyridine-1- carboxylate A1 Int 133 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 366 367-369 (M + H- tBu) 111

tert-butyl 4-(4,5- dichloro-2- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 1-bromo-4,5- dichloro-2- methoxy- benzene +tert- butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 358 N/A 112

tert-butyl 4-(4- chloro-3,5- dimethyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 5-Bromo-2- chloro-1,3- dimethyl- benzene +tert- butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 321 266-268 (M + H- tBu) 113

tert-butyl 4-(4- chloro-3-methyl- phenyl)-3,6- dihydro-2H- pyridine-1-carboxylate A1 4-bromo-1- chloro-2- methyl-benzene + tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 307 N/A 114

tert-butyl 4-(4- chloro-3- methoxy-5- methyl-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 132 + tert- butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 337 282-284 (M + H- tBu) 115

tert-butyl 4-(4- chloro-5-fluoro-2- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 126 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 341 286-288 (M + H- tBu) 116

tert-butyl 4-(5- chloro-4-fluoro-2- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 127 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 341 286-288 (M + H- tBu) 117

tert-butyl 4-(4- chloro-3-ethyl-5- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 131 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 351 296-298 (M + H- tBu) 118

tert-butyl 4-[5-(2- fluorophenyl)-2- thienyl]-3,6- dihydro-2H-pyridine-1- carboxylate A1 Int 123 + 2-(2- fluorophenyl)- tetramethyl-1,3,2- dioxaborolane 359 304 (M + H- tBu) 119

tert-butyl 4-[4- chloro-3- (trifluoromethyl) phenyl]-3,6- dihydro-2H-pyridine-1- carboxylate A1 4-Bromo-1- chloro-2- trifluoromethyl-benzene + tert- butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 361 306-308 (M + H- tBu) 120

tert-butyl 4-(3,5- dichloro-2- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 1-bromo-3,5- dichloro-2- methoxy- benzene +tert- butyl 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate 358 N/A 121

tert-butyl 4-(3- chloro-5- methoxy-phenyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 3-bromo-5- chloroanisole + tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 323 N/A 122

tert-butyl 4-(3,4- dichloro-5- methoxy-phenyl)- 3,6-dihydro-2H-pyridine-1- carboxylate A1 Int 128 + tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 358 N/A 123

tert-butyl 4-(5- chloro-2-thienyl)- 3,6-dihydro-2H- pyridine-1-carboxylate A1 2-bromo-5- chlorothiophene + tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)-3,6-dihydro- 2H-pyridine-1-carboxylate 299 244-246 (M + H- tBu) 124

5-bromo-2- chloro-1,3- dimethoxy- benzene 2.4 1-bromo-4- chloro-3,5-difluorobenzene 251 N/A 125

1-Bromo-4- chloro-2- methoxy-5- methyl-benzene 2.5 1-Bromo-4-chloro-2-fluoro-5- methyl-benzene 235 N/A 126

1-chloro-2-fluoro- 4-iodo-5- methoxy-benzene 2.6 3-chloro-4-fluoroanisole 286 N/A 127

1-chloro-2-fluoro- 5-iodo-4- methoxy-benzene 2.7 4-chloro-3-fluoroanisole 286 N/A 128

5-bromo-1,2- dichloro-3- methoxy-benzene 2.8 1-bromo-3,4- dichloro-5-fluorobenzene 255 N/A 129

5-bromo-1- chloro-2-fluoro-3- methoxy-benzene 2.9 5-Bromo-3- chloro-2-fluorophenol 239 N/A 130

5-bromo-2- chloro-1-ethoxy- 3-methoxy- benzene 2.10 1-bromo-4-chloro-3-fluoro- 5-methoxy- benzene 265 N/A 131

5-bromo-2- chloro-1-ethyl-3- methoxy-benzene 2.11 N-boc-2- methoxyaniline 249 N/A 132

5-bromo-2- chloro-1- methoxy-3- methyl-benzene 2.12 2-methoxy-6-methylaniline 235 N/A 133

5-bromo-2- chloro-3- methoxy-N,N- dimethyl-aniline 2.13 1-bromo-4-chloro-3,5- difluorobenzene 264 264-266 (M + H) 134

5-bromo-2-fluoro- 1,3-dimeoxy- benzene 2.14 1-bromo-3,4- difluoro-5-methoxy- benzene 235 N/A

TABLE III Illustrative compounds of the invention trans:

cis:

Cpd Chemistry Name Mtd SM MW Ms'd 1

(S)-5-[(3-oxo- 3-((4S)- phenylpiperidin- 1-yl)propyl]) imidazolidine-2,4-dione F4 3-[(4S)-2,5- dioxo- imidazolidin-4- yl]propionic acid + 4-phenyl- piperidine 315 316 (M + H) 2

5-[3-oxo-3-(4- phenyl-1- piperidyl) propyl] imidazolidine- 2,4-dione F13-(2,5-dioxo- imidazolidin- 4-yl) propionic acid + 4-phenyl- piperidine315 316 (M + H) 3

5-(3-oxo-3-(4- phenylpiperidin- 1-yl)propyl)- 5-phenyl imidazolidine-2,4-dione F1 3-(4-Phenyl- 2,5-dioxo- imidazolidin-4- yl)propionic acid +4-phenyl- piperidine 391 392 (M + H) 4

5-methyl-5-(3- oxo-3-(4- phenylpiperidin-1- yl)propyl) imidazolidine-2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin-4- yl)propionic acid +4-phenyl- piperidine 329 330 (M + H) 5

5-isopropyl-5- (3-oxo-3-(4- phenylpiperidin-1- yl)propyl) imidazolidine-2,4-dione D Int 15 357 358 (M + H) 6

5-(3-(4-(2- methoxyphenyl) piperidin-1- yl)-3-oxo propyl)-5- methyl-imidazolidine- 2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4- (2-methoxyl- phenyl) piperidine 359 360 (M + H)7

5-cyclopropyl- 5-(3-oxo-3-(4- phenylpiperidin- 1-yl)propyl)imidazolidine- 2,4-dione D Int 14 355 356 (M + H) 8

5-methyl-5-(3- oxo-3-(4-p- tolylpiperidin- 1-yl)propyl) imidazolidine-2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin-4- yl)propionic acid +4-(p- tolyl)piperidine 343 344 (M + H) 9

5-(3-(4-(3,5- dichlorophenyl) piperidin-1- yl)-3- oxopropyl)-5- methyl-imidazolidine- 2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4-(3,5- dichloro- phenyl)piperidine 398 398- 400(M + H) 10

5-(3-(4-(4- fluorophenyl) piperidin-1-yl)- 3-oxopropyl)- 5-methyl-imidazolidine- 2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin- 4-yl)propionic acid + 4- (4-fluoro- phenyl) piperidine- HCl 347 348 (M +H) 11

5-(3-(4-(3- chlorophenyl) piperidin-1- yl)-3- oxopropyl)-5- methyl-imidazolidine- 2,4-dione F1 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4-(3- chlorophenyl) piperidine- HCl 363 364- 366(M + H) 12

5-(3-(4-(4- chlorophenyl) piperidin-1- yl)-3- oxopropyl)-5- methyl-imidazolidine- 2,4-dione F3 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4-(4- chlorophenyl) piperidine- HCl 363 364- 366(M + H) 13

5-(3-(4-(3- fluorophenyl) piperidin-1-yl)- 3-oxopropyl)- 5-methyl-imidazolidine- 2,4-dione F3 3-(4-Methyl- 2,5-dioxo- imidazolidin- 4-yl)propionic acid + 4-(3- fluorophenyl) piperidine 347 348 (M + H) 14

5-(3-(4-(2- fluorophenyl) piperidin-1-yl)- 3-oxopropyl)- 5-methyl-imidazolidine- 2,4-dione F3 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4-(2- fluorophenyl) piperidine- HCl 347 348 (M +H) 15

5-methyl-5-(3- oxo-3-(4-m- tolylpiperidin- 1- yl)propyl) imidazolidine-2,4-dione F3 3-(4-Methyl- 2,5-dioxo- imidazolidin- 4- yl)propionicacid + 4-(m- tolyl)piperidine 343 344 (M + H) 16

5-(3-oxo-3-(4- phenyl- piperidin-1-yl) propyl)- 5-(pyridin-3-yl)imidazolidine- 2,4-dione F1 Int 1 + 4- phenyl- piperidine 392 393(M + H) 17

5-cyclopropyl- 5-(3-(4-(3,5- dichlorophenyl) piperidin-1- yl)-3-oxopropyl) imidazolidine- 2,4-dione F1 Int 2 + 4-(3,5- dichlorophenyl)piperidine 424 424- 426 (M + H) 18

5-(3-(4-(3- chlorophenyl) piperidin-1- yl)-3- oxopropyl)-5- cyclopropyl-imidazolidine- 2,4-dione F1 Int 2 + 4-(3- chlorophenyl) piperidine- HCl389 390- 392 (M + H) 19

5-cyclopropyl- 5-(3-(4-(3- fluorophenyl) piperidin-1-yl)- 3- oxopropyl)imidazolidine- 2,4-dione F1 Int 2 + 4-(3- fluorophenyl) piperidine 373374 (M + H) 20

5-cyclopropyl- 52-methyl-3- oxo-3-(4- phenylpiperidin-1- yl)propyl)imidazolidine- 2,4-dione F3 Int 3 + 4- phenyl)piperidine 369 370 (M + H)21

(R)-5-(3-(4-(4- chloro-3,5- dimethoxy- phenyl)piperidin- 1-yl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int 4 + Int 16 409 410- 412 (M +H) 22

5-(3-(4-(4- chloro-3,5- dimethoxy- phenyl)piperidin- 1-yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4-yl)propionic acid + Int 16 423 424- 426 (M +H) 23

(R)-5-methyl- 5-((S)-2- methyl-3-oxo- 3-(4- phenylpiperidin-1-yl)propyl) imidazolidine- 2,4-dione F2 Int 5 + 4- phenyl- piperidine 343344 (M + H) 24

5-(3-(4-(4- chlorophenyl) piperidin-1- yl)-2-methyl- 3-oxopropyl)-5-methyl imidazolidine- 2,4-dione F2 Int 5 + 4-(4- chlorophenyl)piperidine 377 378- 380 (M + H) 25

5-(3-(4-(3,5- dichlorophenyl) piperidin-1- yl)-2-methyl- 3-oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 Int 5 + 4-(3,5- dichlorophenyl)piperidine 412 412- 414 (M + H) 26

5-(3-(4-(4- fluorophenyl) piperidin-1-yl)- 2-methyl-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 Int 5 + 4-(4- fluorophenyl)piperidine- HCl 361 362 (M + H) 27

5-methyl-5-(2- methyl-3-oxo- 3-(4-m- tolylpiperidin- yl)propyl)imidazolidine- 2,4-dione F2 Int 5 + 4-(3- chlorophenyl) piperidine- HCl357 358- 360 (M + H) 28

5-(3-(4-(3- fluorophenyl) piperidin-1-yl)- 2-methyl-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 Int 5 + 4-(m- tolyl)piperidine 361362 (M + H) 29

5-(3-(4-(3- chlorophenyl) piperidin-1- yl)-2-methyl- 3-oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 Int 5 + 4-(3- fluorophenyl)piperidine 377 378 (M + H) 30

(R)-5-(3-(4-(4- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + 4-(4- methoxyphenyl) piperidine 345346 (M + H) 31

5-(3-(4-(4- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)-5- methyl-imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo- imidazolidin-4-yl)propionic acid + 4-(4- methoxyl- phenyl)piperidine 359 360 (M + H)32

(R)-5-(3-(4-(4- chloro-3- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 17 379 380- 382 (M + H) 33

(R)-5-(3-(4-(4- chloro-5- methoxy-2- methylphenyl) piperidin-1- yl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int 4 + Int 18 393 392- 394 (M +H) 34

(R)-5-(3-(4- (3,5-dimethoxy- phenyl)piperidin- 1-yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 19 375 376 (M + H) 35

(R)-5-(3-(4- (2,5-dimethoxy- phenyl)piperidin- 1-yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 20 375 376 (M + H) 36

5-(3-(4-(4- chloro-3- methoxyl- phenyl)piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 17 393 394- 396 (M + H) 37

5-(3-(4-(4- chloro-5- methoxy-2- methylphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 18 407 390- 392 (M +H) 38

5-(3-(4-(3,5- dimethoxy- phenyl)piperidin- 1-yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 19 389 390 (M + H) 39

5-(3-(4-(2,5- dimethoxy- phenyl)piperidin- 1-yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 20 389 390 (M + H) 40

(R)-5-(3-(4-(5- chloro-2- methoxy- phenyl)piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 21 379 380- 382 (M + H) 41

5-(3-(4-(5- chloro-2- methoxy- phenyl)piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 21 393 394- 396 (M + H) 42

(R)-5-(3-(4-(4- chloro-2- methoxy- phenyl)piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 22 379 380- 382 (M + H) 43

(R)-5-(3-(4- (3,4-difluoro- 5-methoxy- phenyl)piperidin-1- yl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int 4 + Int 23 381 382 (M + H) 44

5-(3-(4-(4- chloro-2- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 22 393 394- 396 (M + H) 45

5-(3-(4-(3,4- difluoro-5- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 23 395 396 (M + H)46

(R)-5-(3-(4-(4- chloro-3- fluoro-5- methoxyphenyl) piperidin-1-yl)-3-oxopropyl) imidazolidine-2,4- dione F2 Int 4 + Int 24 397 398- 400(M + H) 47

5-(3-(4-(4- chloro-3- fluoro-5- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 24 411 412- 414 (M +H) 48

(R)-5-(3-(4- (3,5-dichloro- 2- methylphenyl) piperidin-1- yl)-3-oxopropyl) imidazolidine-2,4- dione F2 Int 4 + Int 25 398 398- 400 (M +H) 49

5-(3-(4-(3,5- dichloro-2- methylphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine-2,4- dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 25 412 412- 414 (M +H) 50

5-(3-(4-(3- fluoro-5- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine-2,4- dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 26 377 378 (M + H) 51

(R)-5-(3-(4-(4- chloro-3- fluorophenyl) piperidin-1- yl)-3-oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 27 367 368- 370 (M + H) 52

(R)-5-(3-(4-(4- fluoro-3- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 28 363 364 (M + H) 53

(R)-5-(3-(4- (3,4- difluorophenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 29 351 352 (M + H) 54

5-(3-(4-(4- chloro-3- fluorophenyl) piperidin-1-yl)- 3-oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 27 381 382- 384 (M + H) 55

5-(3-(4-(4- fluoro-3- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 28 377 378 (M + H) 56

5-(3-(4-(3,4- difluorophenyl) piperidin-1- yl)-3- oxopropyl)-5- methyl-imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo- imidazolidin- 4-yl)propionic acid + Int 29 365 366 (M + H) 57

5-methyl-5-(3- oxo-3-(4-o- tolylpiperidin-1- yl)propyl)imidazolidine-2,4- dione F2 3-(4-Methyl- 2,5-dioxo- imidazolidin- 4-yl)propionic acid + 4-(o- tolyl)piperidine 343 344 (M + H) 58

(R)-5-(3-oxo- 3-(4-o- tolylpiperidin- 1- yl)propyl) imidazolidine-2,4-dione F2 Int 4 + 4-(o- tolyl)piperidine 329 330 (M + H) 59

(R)-5-(3-(4-(4- chloro-2- methylphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine- 2,4-dione F2 Int 4 + Int 30 363 364- 366 (M + H) 60

5-(3-(4-(4- chloro-2- methylphenyl) piperidin-1- yl)-3- oxopropyl)-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 30 377 378- 380 (M + H) 61

(R)-5-(3-(4- (4,5-dichloro- 2- methoxyphenyl) piperidin-1- tl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int 4 + Int 31 414 414- 416 (M +H) 62

5-(3-(4-(4,5- dichloro-2- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 31 428 427- 429 (M +H) 63

(R)-5-(3-(4-(4- chloro-5- fluoro-2- methylphenyl) piperidin-1- yl)-3-oxopropyl) imidazolidine-2,4- dione F2 Int 4 + Int 32 381 382- 384 (M +H) 64

5-(3-(4-(4- chloro-5- fluoro-2- methylphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl-2,5-dioxo- imidazolidin- 4- yl)propionic acid + Int 32 395 396- 398 (M +H) 65

(R)-5-(3-(4- (3,5-dichloro- 2-methoxy phenyl)piperidin- 1-yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F1 Int 6 + Int 52 428 427-429 (M + H) 66

(R)-5-(3-(4-(3- chloro-5- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methyl- imidazolidine- 2,4-dione F1 Int 6 + Int 53 393 394(M + H) 67

(R)-5-(3-(4-(3- chloro-5- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine-2,4- dione F1 Int 4 + Int 53 379 380 (M + H) 68

(R)-5-(3-(4- (3,4-dichloro-5- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methylimidazolidine- 2,4-dione F1 Int 6 + Int 54 428 427-429 (M + H) 69

(R)-5-(3-(4- (3,4-dichloro-5- methoxyphenyl) piperidin-1-yl)-3-oxopropyl) imidazolidine-2,4- dione F1 Int 4 + Int 54 414 413- 451(M + H) 70

(R)-5-(3-(4- (3,5-dichloro-2- methoxyphenyl) piperidin-1- oxopropyl)imidazolidine-2,4- dione F1 Int 4 + Int 52 414 413- 415 (M + H) 71

5-(3-(4-(4,5- dichloro-2- methylphenyl) piperidin-1- yl)-3-oxopropyl)-5- methylimidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 33 412 412- 414 (M + H) 72

5-(3-(4-(4- fluoro-3,5- dimethoxyphenyl) piperidin- 1-yl)-3-oxopropyl)-5- yl)propionic methylimidazolidine- 2,4-dione F23-(4-Methyl- 2,5-dioxo- imidazolidin- 4- acid + Int 34 407 408 (M + H)73

5-(3-(4-(3- chloro-4- fluoro-5- methoxyphenyl) piperidin-1- yl)-3-oxopropyl)-5- methylimidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 35 411 412- 414 (M + H) 74

(R)-5-(3-(4-(3- chloro-2- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)imidazolidine-2,4- dione F1 Int 4 + Int 39 379 380- 382 (M + H) 75

5-(3-(4-(3- chloro-2- methoxyphenyl) piperidin-1- yl)-3- oxopropyl)-5-methylimidazolidine- 2,4-dione F1 Int 6 + Int 39 393 394- 396 (M + H) 76

5-cyclopropyl- 5-(3-((3R,4R)- 4-(3,4- difluorophenyl)- 3-methylpiperidin- 1-yl)-3-oxopropyl) imidazolidine-2,4- dione F2 Int 2 +Int 36 405 406 (M + H) 77

(S)-5-cyclopropyl-5- (3-((3R,4S)-4- (3,4- difluorophenyl)-3-methylpiperidin- 1-yl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int7 + Int 37 405 406 (M + H) 78

(S)-5-cyclopropyl-5- (3-((3R,4R)-4- (3,4- difluorophenyl)-3-methylpiperidin- 1-yl)-3-oxopropyl) imidazolidine- 2,4-dione F2 Int7 + Int 36 405 406 (M + H) 79

(5R)-5-[3-[4- (4-chloro-2- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 22 393394- 396 (M + H) 80

(5R)-5-[3-[4- (3-chloro-4- fluoro-5- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]- 5-methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 35 411412- 414 (M + H) 81

(5R)-5-[3-[4- (4-fluoro-3,5- dimethoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 34 407408 (M + H) 82

(5R)-5-[3-[4- (4-fluoro-3,5- dimethoxy- phenyl)-1- piperidyl]-3-oxo-propyl] imidazolidine- 2,4-dione F2 Int 4 + Int 34 393 408 (M + H)83

(5R)-5-[3-[4- (4-fluoro-5- methoxy-2- methyl-phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 38 391392 (M + H) 84

(5R)-5-[3-[4- (4-chloro-3- fluoro-5- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 24 411412- 414 (M + H) 85

(5R)-5-[3-[4- (4-chloro-3- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 17 393394- 396 (M + H) 86

(5R)-5-[3-[4- (3-chloro-2- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 39 393394- 396 (M + H) 87

(5R)-5-[3-[4- (4-chloro-3- ethoxy-5- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 40 437438- 440 (M + H) 88

(5R)-5-[3-[4- (4-chloro-3- ethoxy-5- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl] imidaz olidine- 2,4-dione F2 Int 4 + Int 40 423 424- 426(M + H) 89

(5R)-5-[3-[4- (4-chloro-2- methoxy-5- methyl- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 41 407408- 410 (M + H) 90

(5R)-5-[3-[4- [4-chloro-3- (dimethylamino)- 5-methoxy- phenyl]-1-piperidyl]-3- oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 +Int 42 436 437- 439 (M + H) 91

(5R)-5-[3-[4- [4-chloro-3- (dimethylamino)- 5-methoxy- phenyl]-1-piperidyl]-3- propyl] imidazolidine- 2,4-dione F2 Int 4 + Int 42 422423- 425 (M + H) 92

5-[3-[4-(4,5- dichloro-2- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- (6-methyl-2- pyridyl) imidazolidine- 2,4-dione F2 Int 8 +Int 43 505 507- 509 (M + H) 93

(5R)-5-[3-[4- (4-chloro-3,5- dimethyl- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 44 391392- 394 (M + H) 94

(5R)-5-[3-[4- [4-chloro-3- (trifluoromethyl) phenyl]-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 51 431 () 95

(5R)-5-[3-[4- (4-chloro-3- methyl- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 45 377378- 380 (M + H) 96

(5R)-5-[3-[4- (4,5-dichloro- 2-methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 43 428428- 430 (M + H) 97

5-[3-[4-(4- chloro-2- methoxy- phenyl)-1- piperidyl]-2- methyl-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 5 + Int 22 407 408-410 (M + H) 98

(5R)-5-[3-[4- (4-chloro-3- methoxy-5- methyl- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 46 407408- 410 (M + H) 99

(5R)-5-[3- [(3R,4R)-4- (3,4- difluorophenyl)- 3-methyl-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 36 379380 (M + H) 100

(5R)-5-[3-[4- (4-chloro-5- fluoro-2- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 47 411412- 414 (M + H) 101

(5R)-5-[3-[4- (5-chloro-4- fluoro-2- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 48 411412- 414 (M + H) 102

5-[3-[4-(4- chloro-3- fluoro-5- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- methyl- imidazolidine- 2,4-dione F2 Int 5 + Int 24 425426- 428 (M + H) 103

5-[3-[4-(4- chloro-3- fluoro-5- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int9 + Int 24 455 456- 458 (M + H) 104

5-[3-[4-(4- chloro-3-ethyl- 5-methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int9 + Int 49 465 466- 468 (M + H) 105

(5R)-5-[3-[4- (4-chloro-3- ethyl-5-methoxy- phenyl)-1- piperidyl]-3-oxo-propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 6 + Int 49 421422- 424 (M + H) 106

(5R)-5-[3-[4- (4-chloro-3- ethyl-5- methoxy- phenyl)-1- piperidyl]-3-oxo-propyl] imidazolidine- 2,4-dione F2 Int 4 + Int 49 407 408- 410 (M +H) 107

5-[3-[4-(5- chloro-4- fluoro-2- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int9 + Int 48 455 456- 458 (M + H) 108

5-[3-[4-(4- chloro-2- methoxy- phenyl)-1- piperidyl]-2- methyl-3-oxo-propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int 9 + Int 22437 438- 440 (M + H) 109

5-[3-[4-(4- chloro-5- fluoro-2- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int9 + Int 47 455 456- 458 (M + H) 110

5-[3-[4-(4- chloro-5- fluoro-2- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 5 + Int47 425 .426- 428 (M + H) 111

5-[3-[4-(5- chloro-4- fluoro-2- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 5 + Int48 425 .426- 428 (M + H) 112

5-[3-[4-[5-(2- fluorophenyl)- 2-thienyl]-1- piperidyl]-3- oxo-propyl]-5-methyl- imidazolidine- 2,4-dione F2 3-(4-Methyl- 2,5-dioxo-imidazolidin- 4- yl)propionic acid + Int 50 429 430 (M + H) 113

5-[3-[4-(4- chloro-3- methoxy-5- methyl- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- methyl- imidazolidine- 2,4-dione F2 Int 5 + Int46 421 422- 424 (M + H) 114

5-[3-[4-(4- chloro-3- methoxy-5- methyl- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione F2 Int9 + Int 46 451 452- 454 (M + H) 115

(5R)-5-[3-[4- (4-chloro-3- methoxy-5- methyl- phenyl)-1- piperidyl]-3-oxo-propyl] imidazolidine- 2,4-dione F2 Int 4 + Int 46 393 394- 396 (M +H) 116

5-[3-[4-(4- chloro-3-fluoro-5- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- methyl- imidazolidine- 2,4-dione D Int 12 425426- 428 (M + H) 117

5-[3-[4-(4- chloro-3-fluoro-5- methoxy- phenyl)-1- piperidyl]-2-methyl-3-oxo- propyl]-5- (methoxymethyl) imidazolidine- 2,4-dione D Int13 455 456- 458 (M + H)

TABLE IV NMR of illustrative compounds of the invention Cpd NMR 43 ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (br. s., 1 H), 6.52-6.78 (m, 2H), 6.37 (d, J = 16.9 Hz, 1 H), 4.81 (d, J = 12.7 Hz, 1 H), 4.21 (q, J =5.7 Hz, 1 H), 4.00 (d, J = 13.2 Hz, 1 H), 3.94 (s, 3 H), 3.18 (t, J =13.2 hz, 1 H), 2.51-2.80 (m, 4 H), 2.25-2.40 (m, 1 H), 2.05-2.23 (m, 1H), 1.93 (d, J = 10.5 Hz, 1 H), 1.43-1.76 (m, 2 H), 1.29 (s, 1 H) 78 ¹HNMR (300 MHz, METHANOL-d₄) δ ppm 6.85- 7.12 (m, 2 H), 6.79 (br. s., 1H), 4.18-4.58 (m, 1 H), 3.50-3.92 (m, 1 H), 1.63-3.31 (m, 10 H),1.34-1.56 (m, 1 H), 0.88-1.18 (m, 2 H), 0.32-0.56 (m, 4 H), −0.10-0.29(m, 3 H) 84 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.63 (br. s., 1 H), 7.92(d, J = 11.2 Hz, 1 H), 6.94 (br. s., 2 H), 4.55 (d, J = 11.2 Hz, 1 H),3.90 (s, 4 H), 3.09 (t, J = 12.3 Hz, 1 H), 2.81 (t, J = 11.9 Hz, 1 H),2.55-2.66 (m, 1 H), 2.34 (d, J = 4.4 Hz, 1 H), 2.22 (d, J = 5.9 Hz, 1H), 1.71-1.95 (m, 4 H), 1.39-1.70 (m, 2 H), 1.29 (s, 3 H) 97 ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.34 (d, J = 8.3 Hz, 1 H), 7.12 (d, J = 8.3 Hz,1 H), 6.94 (ddd, J = 16.8, 8.6, 2.0 Hz, 2 H), 4.71 (d, J = 11.2 Hz, 1H), 4.03-4.22 (m, 1 H), 3.78-3.91 (m, 3 H), 3.44-3.54 (m, 1 H),3.08-3.29 (m, 1 H), 2.61-2.92 (m, 2 H), 2.25-2.54 (m, 1 H), 1.47-1.97(m, 6 H), 1.26-1.44 (m, 3 H), 1.01-1.21 (m, 3 H) 103 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.60 (s, 1 H), 7.04 (s, 1 H), 6.83-6.99 (m, 1 H), 4.59(d, J = 12.2 Hz, 1 H), 3.83-4.09 (m, 4 H), 3.37-3.50 (m, 1 H), 3.17-3.30 (m, 4 H), 2.97-3.14 (m, 2 H), 2.74-2.89 (m, 2 H), 2.54-2.68 (m, 2H), 1.38-1.90 (m, 5 H), 0.88-1.08 (m, 3 H) 104 ¹H NMR (300 MHz,METHANOL-d₄) δ ppm 6.96- 7.06 (m, 1 H), 6.82-6.89 (m, 1 H) 6.73-6.81 (m,1 H), 3.92 (s, 3 H), 3.57 (m, 2 H), 3.44 (m, 2 H), 2.75 (d, J = 7.7 Hz,7 H), 1.77 (br.s., 6 H), 1.02-1.28 (m, 9 H)

BIOLOGICAL EXAMPLES Example 3. In Vitro Assays 3.1. hADAMTS-1

The basis for the assay is the cleavage of the substrate5(6)-Fluorescein-NH-AELQGRPISIAK-5(6)-TAMRA (SEQ ID NO: 1) by humanADAMTS1

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water corresponding to a final highest concentration of 20 μM), istransferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM MOPS pH7; 50 mM NaCl; 5 mM CaCl₂; 0.05% CHAPS; 5 μM ZnCl₂)containing hADAMTS1 (0.38 ng/μL, R&D SYSTEMS INC., Cat#2197-AD)) (itwill be appreciated by the skilled person that the potency read out isindependent of the enzyme concentration).

The reaction is initiated by adding to the assay plate5(6)-Fluorescein-NH-AELQGRPISIAK-5(6)-TAMRA (SEQ ID NO: 1) (10 μL, 7 μM,Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 120 min at 37° C. (Excitation 485 nm, Emission 535).

3.2. hADAMTS-4

Protocol 1

1.1.1 Protocol 1

The basis for the assay is the cleavage of the substrate TBIS-1(5-FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by human ADAMTS4.

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water corresponding to a final highest concentration of 20 μM), istransferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Hepes pH7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS, 5% glycerol)containing hADAMTS4 (0.325 ng/μL) (it will be appreciated by the skilledperson that the potency read out is independent of the enzymeconcentration).The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer. Finally, the fluorescence is readon the Envision (Perkin Elmer) after an incubation of 60 min at roomtemperature (Excitation 485 nm, emission 535).The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

3.3. Protocol 2

The basis for the assay is the cleavage of the substrate TBIS-1 (5FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by human ADAMTS4.

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water corresponding to a final highest concentration of 20 μM), istransferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Hepes pH 7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS) containinghADAMTS4 (0.38 ng/μL) (it will be appreciated by the skilled person thatthe potency read out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 180 min at 37° C. (Excitation 485 nm, emission 535).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

3.4. Rat ADAMTS-5

The basis for the assay is the cleavage of the substrate TBIS-1 (5FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by rnADAMTS-5(1-564-6H).

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM TRIS pH7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS) containingrnADAMTS-5 (0.5 ng/μL) (it will be appreciated by the skilled personthat the potency read out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 120 min at 37° C. (Excitation 485 nm, emission 535).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE V Rat ADAMTS-5 potency of illustrative compounds of the inventionCpd # IC₅₀ (nM) 3 ** 7 ** 9 * 16 ** 17 ** 18 ** 19 *** 20 ** 21 * 22 *23 ** 24 ** 25 *** 26 ** 27 *** 28 **** 29 **** ****0.001-25 nM** >25-50 nM **>50-100 nM *>100 nM

3.5. hADAMTS-5 3.5.1. Protocol 1

The basis for the assay is the cleavage of the substrate TBIS-1 (5FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by human ADAMTS-5.

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Hepes pH7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS, 5% glycerol)containing hADAMTS-5 (0.5 ng/μL) (it will be appreciated by the skilledperson that the potency read out is independent of the enzymeconcentration).

The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 60 min at Room Temperature (Excitation 485 nm, emission530).

3.5.2. Protocol 2

The basis for the assay is the cleavage of the substrate TBIS-1 (5FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by human ADAMTS-5.

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Hepes pH7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS 1) containinghADAMTS-5 (1 ng/μL, affinity purified, followed by overnight digestionof 6His tag by thrombin and dialysis) (it will be appreciated by theskilled person that the potency read out is independent of the enzymeconcentration).

The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 45 min at 37° C. (Excitation 485 nm, emission 530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

hADAMTS-5 potency of illustrative compounds of the invention

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE VI hADAMTS-5 potency of illustrative compounds of the inventionCpd # IC₅₀ (nM) 1 * 2 * 3 ** 4 * 5 ** 6 * 7 ** 8 * 9 ** 10 * 11 * 12 *13 * 14 * 15 * 16 ** ****0.001-25 nM ** >25-50 nM **>50-100 nM *>100 nM

3.5.3. Protocol 3

The basis for the assay is the cleavage of the substrate TBIS-1 (5FAM-TEGEARGSVILLK (5TAMRA)K-NH₂) (SEQ ID NO: 2) by human ADAMTS-5.

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Hepes pH 7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1% CHAPS) containinghADAMTS-5 (0.63 ng/4) (it will be appreciated by the skilled person thatthe potency read out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate TBIS-1 (10 μL,4.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 90 min at 37° C. (Excitation 485 nm, emission 530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE VII hADAMTS-5 potency of illustrative compounds of the inventionCpd # IC₅₀ (nM) 17 ** 18 *** 19 *** 20 ** 21 * 22 * 23 ** 24 ** 25 ***26 ** 27 *** 28 *** 29 *** 30 * 31 * 32 * 33 * 34 * 35 * 36 * 37 * 38 *39 * 40 * 41 * 42 * 43 * 44 * 45 * 46 ** 47 ** 48 * 49 * 50 * 51 * 52 *53 * 54 * 55 * 56 * 57 * 58 * 60 * 61 * 62 * 63 * 64 * 65 * 66 * 67 * 68** 69 ** 70 * 71 * 72 * 73 * 74 * 75 * 76 ** 77 * 78 *** 79 * 80 ** 81** 82 * 84 *** 85 ** 86 * 87 * 88 * 89 * 90 * 93 * 96 * 97 * 98 ** 99 **100 * 101 * 102 *** 103 **** 104 *** 105 * 106 * 107 ** 108 ** 109 **110 ** 111 ** 112 * 113 *** 114 *** 115 * ****0.001-25 nM ** >25-50 nM**>50-100 nM *>100 nM

3.6. hADAMTS-6 3.6.1. Preparation of hADAM-TS6 Protein 3.6.1.1. ADAMTS-6Protein Expression

The coding sequence from amino acid 1 to 843 of the human ADAMTS6protein (UniProtKB/Swiss-Prot Q9UKP5, SEQ ID NO: 4) is cloned into thepYD7 vector (vectors and the expression system are described in(Durocher et al., 2002; Loignon et al., 2008; Shi et al., 2005))(CNRC-NRC) in Cterminal fusion with a sequence containingTev-GGGGGS-Thr-6his (SEQ ID NO: 5)(pYD7-HsADAM-TS6(1-843)-Tev-GGGGGS-Thr-6his construct). Durocher's293-6E cells (CNRC-NRC) are grown in suspension at 37° C. in ahumidified incubator containing 5% CO₂ at 37° C. in F17 culture medium(Invitrogen # A1383501) supplemented with 10 mL/L of 10% Pluronic F68solution (0.1% final) (Invitrogen #24040032), 20 mL/L of 200 mML-Glutamine solution (4 mM final) (Lonza # BE17-605E) and 25 μg/mL G418(PAA laboratories # P11-012).

Transfection is performed according to the protocol given by CNRC-NRCfor the 293-6E cells using PEI (Polysciences #23966-2). Cells arediluted to 3.105 cells/mL three days before transfection.

On the day of transfection, the cell density is adjusted to 17.105cells/mL. A DNA/PEI mix is prepared according to CNRC-NRCrecommendations with a ratio of DNA/PEI of 1 for 2, meaning, 300 μg ofpYD7-HsADAM-TS6(1-843)-Tev-GGGGGS-Thr-6his construct and 600 μg PEI for300 mL of final transfection volume. The day after transfection, Heparin(Sigma # H3149) and TN1 (Teckniscience Inc. #19553) is added to get 0.1g/L and 0.5% final concentrations respectively.

The conditioned medium is harvested 168 h post-transfection bycentrifugation for 20 min at 5000×g at 4° C. The expression level ofsecreted HsADAM-TS6 is estimated at 1 mg/L in the conditioned medium(CM) by Western blotting analysis using anti His tag primary antibody.Conditioned medium is either used from fresh or frozen production at−20° C. for later use.

3.6.1.2. Purification of HsADAM-TS6 Protein

10× buffer A (500 mM Tris pH 8, 4 M NaCl, 10 mM CaCl₂, 10 μM ZnCl₂, 0.5%CHAPS, 200 mM imidazole) is slowly added to the conditioned medium undermagnetic stirring, giving Buffered Conditioned Medium (BCM). This sampleis clarified by centrifugation at 15,000×g for 60 min at 4° C. in aBeckman 16.250 rotor, providing the starting sample.

Affinity purification is performed using ÄKTA protein purificationsystem (GE Healthcare) in 4° C. cabinet. 400 mL of the start sample isloaded onto each HisTrap™ HP 5 mL column (GE Healthcare #17-5248-02) ata flow rate of 5 mL/min. The resin is then washed with equilibrationbuffer B (50 mM Tris (pH 8), 0.5 M NaCl, 1 mM CaCl₂, 1 μM ZnCl₂, 20 mMimidazole, 0.05% CHAPS) until the absorbance at 280 nm returns to zero.The elution is then performed with 70 mM imidazole (elution ofcontaminant proteins) and subsequently 300 mM imidazole (elution of thetarget protein). The fractions containing the non-mature (1-843) ADAMTS6protein are pooled and subjected to 2 dialyses against 100 volumes ofdialysis buffer C (50 mM Tris pH 8+100 mM NaCl+1 mM CaCl₂+1 μMZnCl₂+0.1% Polyoxyethyleneglycol Dodecyl Ether [Brij 35]) using 50 kDacut off membrane (SpectraPor #132 542). This allows to decrease the NaClconcentration for efficient furin cleavage.

3.6.1.3. Maturation of HsADAM-TS6 Protein

In vitro maturation of human ADAMTS6 protein is performed using furin(R&D #1503-SE) (3 ng furin/μg of target protein), in buffer D (25 mMTris pH 9+100 mM NaCl+1 mM CaCl₂+1 μM ZnCl₂+0.5% Brij 35). Incubation isconducted overnight at room temperature.

The furin cleaved sample is subsequently dialyzed for 1 hour against 100volumes of dialysis buffer C. Finally, 10% glycerol is added to thefinal batch which is subsequently ultracentrifuged for 30 minutes at35,000 rpm using a Beckman SW41Ti rotor and stored at −80° C.

Following this procedure the final yield reached an average of 0.05 to0.1 mg matured human ADAMTS6 (SEQ ID NO: 6)/L of culture medium.

3.6.2. hADAMTS-6 Assay

The IC₅₀ value for test compounds can be determined in a fluorescentbased protease assay.

The basis for the assay is the cleavage of the substrate 520 MMP FRETsubstrate XII by human ADAMTS6.

The substrate contains sequence Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(SEQ ID NO: 7) with attached a fluorescent probe and a quencher. WithoutADAMTS6, the emission of the probe is quenched. If the substrate iscleaved by ADAMTS6, the emission of the probe is not quenched anymore.Inhibition of ADAMTS6 activity, will result in a decrease of the signal.

To perform the assay, 4 μL of a dilution series of compound in water,starting from 20 μM highest concentration, 1/5 dilution, is added to thewells. 2 ng ADAMTS6 enzyme is diluted in 25 mM Tris pH8.0, 0.05% CHAPS,2.5 mM CaCl₂ in a total volume of 26 μL (final concentration 0.73 nM).The reaction is started by addition of 10 μL of 1 μM 520 MMP FRETSubstrate XII (final concentration, diluted in same buffer as describedabove) and the mixture is incubated at 37° C. for 2 h. The negativecontrol (0% inhibition) is 1% DMSO and the positive control (100%inhibition) is 10 μM Prinomastat in 1% DMSO. After this incubation,cleavage of the substrate is measured using the Envision (Perkin Elmer,exc485/em530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE VIII hADAMTS-6 potency of illustrative compounds of the inventionCpd # IC₅₀ (nM) 1 * 2 * 3 * 4 * 5 * 6 * 7 * 8 * 9 *** 10 * 11 ** 12 **13 * 14 * 15 * 16 * 17 ** 18 * 19 * 20 * 21 **** 22 **** 23 ** 24 ****25 **** 26 *** 27 *** 28 ** 29 *** 30 * 31 * 32 *** 33 *** 34 ** 35 * 36**** 37 **** 38 *** 39 * 40 * 41 ** 42 *** 43 *** 44 **** 45 **** 46**** 47 **** 48 ** 49 *** 50 ** 51 ** 52 * 53 * 54 ** 55 ** 56 * 57 *58 * 59 * 60 ** 61 **** 62 **** 63 ** 64 *** 65 ** 66 **** 67 ** 68 ****69 **** 70 * 71 **** 72 **** 73 **** 74 * 75 * 76 ** 77 * 78 *** 79 ****80 **** 81 **** 82 **** 83 *** 84 **** 85 **** 86 * 87 **** 88 **** 89**** 90 **** 91 *** 92 **** 93 **** 94 *** 95 **** 96 **** 97 **** 98**** 99 *** 100 **** 101 *** 102 **** 103 **** 104 **** 105 **** 106**** 107 **** 108 **** 109 **** 110 **** 111 **** 112 ** 113 **** 114**** 115 **** ****0.001-25 nM ** >25-50 nM **>50-100 nM *>100 nM

3.6.3. hTACE

The basis for the assay is the cleavage of the substrate5FAM-LAQAVRSSSRK-5TAMRA (SEQ ID N^(o) 3) (Anaspec, custom 34891) byhuman TACE (R&D SYSTEMS INC., Cat#930-ADB).

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(25 mM Tris pH8.0, 2.5 μM ZnCl₂, 0.01% CHAPS) containing TACE (0.05ng/μL) (it will be appreciated by the skilled person that the potencyread out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate5FAM-LAQAVRSSSRK-5TAMRA (5 μL, 5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 75 min at room temperature (Excitation 485 nm, Emission530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE IX hTACE potency of illustrative compounds of the invention Cpd #IC₅₀ (nM) 2 * 3 * 4 * 5 * 7 * 9 * 10 * 11 * 12 * 16 * 17 * 18 * 19 *20 * 21 * 22 ** 23 * 24 * 25 ** 26 * 27 ** 28 * 29 ** 32 * 33 * 34 *36 * 37 * 38 * 41 ** 42 * 43 * 44 * 45 * 46 * 47 * 48 * 49 * 50 * 51 *52 * 54 * 55 * 57 * 58 * 61 * 62 * 64 * 65 ** 66 *** 67 ** 68 ** 69 **70 * 71 ** 72 * 73 * 74 * 75 * 76 * 77 * 78 * 79 * 80 *** 81 *** 82 **84 ** 85 ** 87 ** 88 ** 89 ** 90 ** 93 ** 96 ** 97 * 98 *** 100 * 101 *102 ** 103 ** 104 ** 105 *** 106 ** 107 ** 108 ** 109 ** 110 ** 111 **113 ** 114 ** 115 ** ****0.001-25 nM ** >25-50 nM **>50-100 nM *>100 nM

3.6.4. hMMP1

Inhibition of the proteases human MMP1 was determined at REACTIONBIOLOGY (Reaction Biology Corp. 1 Great Valley Parkway, Suite 2 Malvern,Pa. 19355, USA) in fluorescent based biochemical assays. The proteaseactivities were monitored as a time-course measurement of the increasein fluorescence signal from fluorescently-labeled peptide substrates,and initial linear portion of slope (signal/min) was analyzed.

To determine the IC₅₀, a compound is tested starting from 100 nM(highest dilution) with a 1/3 dilution.

3.6.5. hMMP2 3.6.5.1. Protocol 1

The basis for the assay is the cleavage of the substrate 520 MMP fretsubstrate XV (Anaspec, Catalog #: AS-60582-01) by human MMP2 (R&DSYSTEMS INC. Systems Inc., Cat#902-MP).

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Tris pH 7.5, 10 mM, CaCl₂, 150 mM NaCl, 0.05% Brij35) containingpreactivated MMP2 (0.0125 ng/μL) (it will be appreciated by the skilledperson that the potency read out is independent of the enzymeconcentration). Human MMP2 is preactivated by incubated the enzyme inthe same buffer complemented with 1 mM freshly preparedp-Aminophenylmercuric acetate (AMPA) for 1 h at 37° C.

The reaction is initiated by adding to the assay plate 520 MMP fretsubstrate XV (10 μL, 4 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 30 min at room temperature (Excitation 485 nm, Emission530).

3.6.5.2. Protocol 2

The basis for the assay is the cleavage of the substrate 390 MMP FRETsubstrate I (Anaspec, Catalog n#: AS-27076) by human MMP2 (R&D SYSTEMSINC., Cat#902-MP).

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(45 mM Tris pH 7.5, 9 mM CaCl₂, 135 mM NaCl, 0.045% Brij35) containingMMP2 (0.03 ng/μL) (it will be appreciated by the skilled person that thepotency read out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate 390 MMP FRETsubstrate I (10 μL, 2.5 μM, Anaspec) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 30 min at room temperature (Excitation 485 nm, Emission530).

3.6.6. hMMP8

Inhibition of the human MMP8 protease is determined at REACTION BIOLOGY(Reaction Biology Corp. 1 Great Valley Parkway, Suite 2 Malvern, Pa.19355, USA; cat# MMP8) in fluorescence based biochemical assays. Theprotease activity is monitored as a time-course measurement of theincrease in fluorescence signal from fluorescently-labeled peptidesubstrates, and the slope (signal/min) of the initial linear portion ismeasured.

The basis for the assay is the cleavage of the substrate 520 MMP FRETSubstrate XIV (Anaspec, cat# AS-60581) by human MMP8 (Enzo®, cat#SE-255) in a buffer solution (50 mM HEPES pH 7.5, 10 mM CaCl₂, 0.01%Brij-35, 0.1 mg/mL BSA).

A 100% DMSO dilution series of test compound (10 final concentrationsstarting from 30 μM highest concentration, with 1/3 serial dilutions) isadded to MMP8 in buffer solution and incubated at room temperature for5-15 min (it will be appreciated by the skilled person that the potencyread out is independent of the enzyme concentration). The reaction isthen initiated by adding 520 MMP FRET Substrate XIV (5 μM finalconcentration) in the same buffer.

Fluorescence is read at 5 min intervals for 2 h with an Envision (PerkinElmer) at room temperature (Excitation 485 nm, Emission 520 nm). Theslope of the initial linear portion of the fluorescence signal curve isthen calculated by using Excel. Percent protease activity is calculatedrelative to a no inhibitor DMSO control defined as 100% activity. IC₅₀curve fits are performed using Prism software.

3.6.7. hMMP12

Inhibition of the human MMP12 protease is determined at REACTION BIOLOGY(Reaction Biology Corp. 1 Great Valley Parkway, Suite 2 Malvern, Pa.19355, USA; cat# MMP12) in fluorescence based biochemical assays. Theprotease activity is monitored as a time-course measurement of theincrease in fluorescence signal from fluorescently-labeled peptidesubstrates, and the slope (signal/min) of the initial linear portion ismeasured.

The basis for the assay is the cleavage of the substrate 520 MMP FRETSubstrate XIV (Anaspec, cat# AS 60581) by human MMP12 (Enzo®, cat#SE-138) in a buffer solution (50 mM HEPES pH 7.5, 10 mM CaCl₂, 0.01%Brij-35, 0.1 mg/mL BSA).

A 100% DMSO dilution series of test compound (10 final concentrationsstarting from 30 μM highest concentration, with 1/3 serial dilutions) isadded to MMP12 in buffer solution and incubated at room temperature for5-15 min (it will be appreciated by the skilled person that the potencyread out is independent of the enzyme concentration). The reaction isthen initiated by adding 520 MMP FRET Substrate XIV (5 μM finalconcentration) in the same buffer.

Fluorescence is read at 5 min intervals for 2 h with an Envision (PerkinElmer) at room temperature (Excitation 485 nm, Emission 520 nm). Theslope of the initial linear portion of the fluorescence signal curve isthen calculated by using Excel. Percent protease activity is calculatedrelative to a no inhibitor DMSO control defined as 100% activity. IC₅₀curve fits are performed using Prism software.

3.6.8. hMMP13 3.6.8.1. Protocol 1

The basis for the assay is the cleavage of the substrate 390 MMP FRETSubstrate I (Anaspec Cat# AS-27076) by human MMP13 (Chemicon,Cat#CC068).

For the dose response (10 point), 4 μL of a dilution series of compound(20 μM highest concentration, 1/5 dilution in water), is transferred to384 well Fluotrac 200 plate (Greiner, cat#781076) and incubated at roomtemperature for 30 min with a 26 μL buffer solution (50 mM Tris pH7.5,150 mM NaCl, 10 mM CaCl₂, 0.05% CHAPS, 5 μM ZnCl₂) containing MMP13(0.01 ng/μL) (it will be appreciated by the skilled person that thepotency read out is independent of the enzyme concentration). HumanMMP13 is preactivated by incubated the enzyme in the same buffercomplemented with 1 mM freshly prepared p-Aminophenylmercuric acetate(AMPA) for 1 h at 37° C.

The reaction is initiated by adding to the assay plate 390 MMP FRETSubstrate I (10 μL, 2.5 μM) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 45 min at room temperature (Excitation 485 nm, Emission530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE X hMMP-13 potency of illustrative compounds of the invention Cpd #IC₅₀ (nM) 7 * 9 * 10 * 11 * 12 * 16 * 17 * 18 * 19 * 20 * 21 * 22 * 23 *24 * 25 * 26 * 27 * 28 * 29 * 32 * 33 * 34 * 36 * 37 * 38 * 41 * 42 *43 * 44 * 45 * 46 * 47 * 48 * 49 * 50 * 51 * 54 * 55 * 57 * 58 *****0.001-25 nM ** >25-50 nM **>50-100 nM *>100 nM

3.6.8.1. Protocol 2

The basis for the assay is the cleavage of the substrate 390 MMP FRETSubstrate I (Anaspec Cat# AS-27076) by human MMP13 (Chemicon,Cat#CC068).

For the dose response (10 point), 4 μL of a dilution series of compound(20 μM highest concentration, 1/5 dilution in water), is transferred to384 well Fluotrac 200 plate (Greiner, cat#781076) and incubated at roomtemperature for 30 min with a 26 μL buffer solution (50 mM Tris pH7.5,150 mM NaCl, 10 mM CaCl₂, 0.05% CHAPS, 5 μM ZnCl₂) containing MMP13(0.01 ng/μL) (it will be appreciated by the skilled person that thepotency read out is independent of the enzyme concentration). HumanMMP13 is preactivated by incubated the enzyme in the same buffercomplemented with 1 mM freshly prepared p-Aminophenylmercuric acetate(AMPA) for 1 h at 37° C.

The reaction is initiated by adding to the assay plate 390 MMP FRETSubstrate I (10 μL, 2.5 μM) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 45 min at room temperature (Excitation 485 nm, Emission530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE XI hMMP-13 potency of illustrative compounds of the invention Cpd# IC₅₀ (nM) 61 * 62 * 64 * 65 * 66 * 67 * 68 * 69 * 70 * 71 * 72 * 73 *74 * 75 * 79 * 80 * 81 * 82 * 84 * 85 * 87 * 89 * 90 * 93 * 96 * 97 *98 * 100 * 101 * 102 * 103 * 104 * 105 * 106 * 107 * 108 * 109 * 110 *111 * 113 * 114 * 115 * ****0.001-25 nM ** >25-50 nM **>50-100 nM *>100nM

3.6.8.2. Protocol 3

The basis for the assay is the cleavage of the substrate 520 MMP-fretsubstrate XV (Anaspec, Catalog #: AS-60582-01) by human MMP13 (Chemicon,Cat# CC068).

For the dose response (10 point), 4 μL of a dilution series of compound(2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in10 in water, corresponding to a final highest concentration of 20 μM),is transferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM Tris pH7.5, 150 mM NaCl, 10 mM CaCl₂, 0.05% CHAPS, 5 μM ZnCl₂)containing MMP13 (6.25 10⁻⁶ μg/μL) (it will be appreciated by theskilled person that the potency read out is independent of the enzymeconcentration).

The reaction is initiated by adding to the assay plate 520 MMP-fretsubstrate XV (10 μL, 4 μM) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 60 min at room temperature (Excitation 485 nm, Emission530).

3.6.9. hMMP14

The basis for the assay is the cleavage of the substrate 390 MMP FRETSubstrate I (Anaspec Cat# AS-27076) by human MMP14 (Biomol, Cat#SE-259).

For the dose response (10 point), 4 μL of a dilution series of compound2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in 10in water, corresponding to a final highest concentration of 20 μM), istransferred to 384 well Fluotrac 200 plate (Greiner, cat#781076) andincubated at room temperature for 30 min with a 26 μL buffer solution(50 mM MOPS pH7, 5 mM CaCl₂, 1 μM ZnCl₂, 0.1% Brij-35) containing MMP14(0.05 ng/μL) (it will be appreciated by the skilled person that thepotency read out is independent of the enzyme concentration).

The reaction is initiated by adding to the assay plate 390 MMP FRETSubstrate I (10 μL, 2.5 μM) in the same buffer.

Finally, the fluorescence is read on the Envision (Perkin Elmer) afteran incubation of 60 min at room temperature (Excitation 485 nm, Emission530).

The IC₅₀ measured for illustrative compounds of the invention isreported in the table below.

TABLE XII hMMP-14 potency of illustrative compounds of the invention Cpd# IC₅₀ (nM) 42 * 44 * 51 * 54 * 55 * 61 * 62 * 64 * 71 * 72 * 73 * 74 *75 * 79 * 80 * 81 * 82 * 84 * 85 * 87 * 89 * 90 * 93 * 96 * 97 * 98 *100 * 101 * 102 * 103 * 104 * 105 * 106 * 107 * 108 * 109 * 110 * 111 *113 * 114 * 115 * ****0.001-25 nM ** >25-50 nM **>50-100 nM *>100 nM

3.7. Cellular Assays 3.7.1. Mouse Explant Assay

In this assay, quantitation of glycosaminoglycans (GAGs) in the form ofaggrecan fragments released from cartilage in culture is used todetermine the efficacy of a test compound in preventing cartilagecatabolism.

The protocol of mouse cartilage explants is described by Stanton(Stanton et al., 2011). After euthanasia, the femoral head cartilagefrom the right and left leg of a 3-days-old C57B16 male mouse (Janvier,7-10 g), were placed in a 48-wells culture plate. Cell culture medium(4004) containing human IL1α (1 ng/mL) and test compound (3 μM) wereadded to the femoral head cartilage.

After 3 days of incubation, the supernatant is harvested and stored at−20° C. until analysis and the cartilages are digested with a papainsolution at 60° C. for 24 h. Using the standard curve performed with adose range of chondroitin sulfate, the concentration of GAG isdetermined in the supernatant and on the lysate using dimethylmethyleneblue solution (reading at a wavelength of 590 nm).

The percentage of GAG release is calculated as follows:

${{GAG}\mspace{14mu}\%} = \frac{\lbrack{GAG}\rbrack_{supernatant}}{\lbrack{GAG}\rbrack_{supernatant} + \lbrack{GAG}\rbrack_{lysate}}$

The test compound effect is expressed as percent of inhibition (PIN)using the following formula:

${PIN} = {\frac{{{mean}\mspace{14mu}{\%\mspace{11mu}\lbrack{GAG}\rbrack}_{{vehicle} + {{IL}\; 1\alpha}}} - {{mean}\mspace{14mu}{\%\mspace{11mu}\lbrack{GAG}\rbrack}_{{compound} + {{IL}\; 1\alpha}}}}{{{mean}\mspace{14mu}{\%\mspace{11mu}\lbrack{GAG}\rbrack}_{{vehicle} + {{IL}\; 1\alpha}}} - {{mean}\mspace{14mu}{\%\mspace{11mu}\lbrack{GAG}\rbrack}_{compound}}}*100}$

3.7.2. Human Explant Assay

In this assay, compounds are tested in human articular cartilageexplants in order to evaluate their activity on aggrecan degradationinduced by IL1β. AGNx1 is the epitope for aggrecanase-mediated aggrecandegradation; on the other hand, AGNx2 is the epitope for MMP-mediatedaggrecan degradation. Therefore quantification of AGNx1 and AGNx2 may beused to evaluate the activity of a test compound.

These studies were conducted in Nordic Bioscience (Herlev Hovedgade 207,DK-2730 Herlev, Denmark).

Human articular cartilage explants are collected from 3 nearby hospitalsunder an existing ethical committee application.

Full-depth cartilage explants from OA cartilage from different patientsare cultured for 21 days in culture medium (DMEM/F12 with 0.5% FCS, 1%PS) containing various (positive control, untreated, and test compoundat 0.1, 1 and 10 μM).

The explants from each patient are cultured in a separate 96-wellculture plate with 2004/well PBS, and the 6 replicates of each treatmentare distributed in a diagonal pattern on the plate. At each experimentaltime point (5, 12 and 19 days), supernatants are harvested from theexplants cultures, and new treatment-mediums are added. The supernatantsare stored at −20° C. for later biomarker analysis. The human IL113(Sigma-Aldrich SRP3083) is used at a concentration of 10 ng/mL.

3.7.3. Results

The AGNx1 and AGNx2 concentrations were determined against a standardcurve. Mean and SEM were graphed using the excel software. One-way ANOVAplus Dunnett's multiple comparisons post-hoc test are used for thestatistical analysis (Prism 3.03 software).

3.8. In Vivo Assays 3.8.1. In Vivo Menisectomized (MNX) Rat Model3.8.1.1. In Vivo Efficacy in the Rat MNX Model

In vivo efficacy was studied in a female Lewis meniscectomised rat (MNX)model. The MNX rat model is a well-validated disease model ofosteoarthritis (Bendele, 2001; Janusz et al., 2002; Pritzker et al.,2006).

3.8.1.2. Experimental Procedures 3.8.1.2.1 Surgery and Dosing

Osteoarthritis is induced by meniscectomy at day 0 (DO) in the right legof each rat by a transection of the medial collateral ligament and 4 mmof ligament are removed. Internal part of the meniscus is transectedvertically into two flaps which are pushed to the front and the back ofthe synovial cavity. Sham animals undergo only anaesthesia, skin andmuscle incision then suture. On day 1, rats are randomly assigned to atreatment group (n=20 per group) according to their body weight, inorder to have a homogenous distribution. From D2 to D21, rats are dosedper os (po) once daily (qd) or twice a day (bid) with compoundsformulated in methylcellulose (MC) 0.5% or in HPβCD 10% pH3.0.

3.8.1.2.2 Steady-State PK Determination (ssPK)

After at least 7 days of treatment, blood is sampled at 4 time pointspost administration: 0, 1, 3 and 6 h (and assuming 24 h is equal to thepre-dose sample), in order to determine steady-state plasma exposure.

3.8.1.2.3 Histology

At sacrifice, the right tibia of each rat is collected and processed forhistological analysis. After 48 h of fixation in 4% formaldehyde, tibiasare decalcified in Osteosoft for 7 days, and cut into 2 half parts priorto embedding face to face in paraffin. Five series of sections are cutat 200 μm intervals, covering about 1.5 mm of the middle part of thebone. One series of slides is stained with Safranin 0 and light greenfor morphological evaluation and OARSI scoring. The other series ofslides are mounted with DAPI for chondrocyte density measurement.

The extent of cartilage injury reflecting osteoarthritis in the tibialplateau is evaluated and scored using the OARSI method based on thegrading and the staging of cartilage lesion (Pritzker et al, 2006). TheOARSI scoring is assessed in a blinded manner by two different readers.For each tibia, one score is attributed as the median of the OARSI scoreof the 5 sections.

For statistical analysis, medians of groups are compared with astratified Kruskal-Wallis test followed by Dunnett multiple comparisonpost hoc test.

Significance levels: ns: not statistically significant; *p<0.05;**p<0.01; ***p<0.001 versus MNX-vehicle. Statistical analyses are doneon all groups of the studies.

FINAL REMARKS

It will be appreciated by those skilled in the art that the foregoingdescriptions are exemplary and explanatory in nature, and intended toillustrate the invention and its preferred embodiments. Through routineexperimentation, an artisan will recognize apparent modifications andvariations that may be made without departing from the spirit of theinvention. All such modifications coming within the scope of theappended claims are intended to be included therein. Thus, the inventionis intended to be defined not by the above description, but by thefollowing claims and their equivalents.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication are specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It should be understood that factors such as the differential cellpenetration capacity of the various compounds can contribute todiscrepancies between the activity of the compounds in the in vitrobiochemical and cellular assays.

At least some of the chemical names of compound of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified.Representative programs performing this function include the Lexichemnaming tool sold by Open Eye Software, Inc. and the Autonom Softwaretool sold by MDL, Inc. In the instance where the indicated chemical nameand the depicted structure differ, the depicted structure will control.

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The invention claimed is:
 1. A compound according to Formula I:

wherein R¹ is: H, C₁₋₄ alkyl optionally substituted with one or moreindependently selected R⁴ groups, C₃₋₇ monocyclic cycloalkyl optionallysubstituted with one or more independently selected R⁴ groups, 4-7membered monocyclic heterocycloalkyl comprising 1 to 2 heteroatomsindependently selected from N, O, and S, optionally substituted with oneor more independently selected C₁₋₄ alkyl, —C(═O)C₁₋₄ alkyl, or—C(═O)OC₁₋₄ alkyl, phenyl optionally substituted with one or moreindependently selected R⁵ groups, phenyl fused to a 5-6 memberedmonocyclic heterocycloalkyl comprising 1, 2 or 3 heteroatomsindependently selected from N, O, and S, which heterocycloalkyl isoptionally substituted with one or more ═O, 5-6 membered monocyclicheteroaryl comprising 1 or 2 heteroatoms independently selected from N,O, and S, optionally substituted with one or more independently selectedR⁵ groups; R² is independently selected from: H, OH, C₁₋₄ alkoxy, andC₁₋₄ alkyl optionally substituted with one OH, —CN, C₁₋₄ alkoxyoptionally substituted with one phenyl, and 5-6 membered monocyclicheteroaryl comprising 1 or 2 heteroatoms independently selected from N,O, and S, optionally substituted with one or more independently selectedC₁₋₄ alkyl; each R^(3a), and R^(3b) is independently selected from H,and C₁₋₄ alkyl; Cy is 6-10 membered monocyclic or fused bicyclic aryl,5-10 membered monocyclic or fused bicyclic heteroaryl comprising 1, 2 or3 heteroatoms independently selected from N, O, and S; R⁴ is halo, OH,—CN, C₁₋₄ alkyl, C₁₋₄ alkoxy optionally substituted with one C₁₋₄alkoxy, or phenyl, C₁₋₄ thioalkoxy, 4-7-membered monocyclicheterocycloalkyl comprising one or more heteroatoms independentlyselected from N, S, and O, optionally substituted with one or more halo,or —C(═O)OC₁₋₄ alkyl, phenyl, —S(═O)₂C₁₋₄ alkyl —C(═O)OR^(7a)—C(═O)NR^(7b)R^(7c) —NHC(═O)OR^(7d) —NHC(═O)R^(7e) —NR^(8a)R^(8b); eachR⁵ is halo, OH, —CN, —C₁₋₄ alkyl optionally substituted with one or moreindependently selected halo, —NR^(9a)R^(9b), or —C(═O)NR^(9c)R^(9d),C₁₋₄ alkoxy optionally substituted with —NR^(9e)R^(9f), or —S(═O)₂C₁₋₄alkyl; the subscript n is 0, 1, 2 or 3; each R⁶ is independentlyselected from: halo, —CN, —NO₂, —C₁₋₄ alkyl optionally substituted withone or more halo, —C₁₋₄ alkoxy optionally substituted with one or morehalo, 5-10 membered monocyclic or fused bicyclic heteroaryl comprising1, 2 or 3 heteroatoms independently selected from N, O, and S,optionally substituted with one or more independently selected halo,C₁₋₄ alkyl, or C₁₋₄ alkoxy, and —NR^(9g)R^(9h); each R^(7a), R^(7b),R^(7c), R^(7d), or R^(7e), is H, or C₁₋₄ alkyl optionally substitutedwith one OH or C₁₋₄ alkoxy; each R^(8a), or R^(8b) is independentlyselected from H, and C₁₋₄ alkyl optionally substituted with OH, C₁₋₄alkoxy, or phenyl; each R^(9a), R^(9b), R^(9c), R^(9d), R^(9e), R^(9f),R^(9g), and R^(9h) is independently selected from H, and C₁₋₄ alkyl; ora pharmaceutically acceptable salt, or a solvate, or a pharmaceuticallyacceptable salt of a solvate thereof; or a biologically activemetabolite thereof; provided that the compound is not5-[3-oxo-3-[4-(4-pyridinyl)-1-piperidinyl]propyl]-2,4-ImidazolidinedioneCAS#1422565-71-6,5(S)-[3-oxo-3-[4-(1H-1,2,4-triazol-5-yl)-1-piperidinyl]propyl]-2,4-imidazolidinedioneCAS#1638335-41-7,5(S)-[3-[4-(2-methoxyphenyl)-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1781306-72-6,5-[3-[4-(5-methyl-4-pyrimidinyl)-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1638336-99-8,5-[3-[4-(7-methyl-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1422561-83-8,5-[3-[4-(6-fluoro-1H-benzimidazol-2-yl)-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1377848-53-7,5-[3-[4-(3,5-dimethylimidazo[5,1-b]thiazol-7-yl)-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1287426-16-7, or5-[3-[4-[4-methyl-5-(2-methyl-4-pyrimidinyl)-2-thiazolyl]-1-piperidinyl]-3-oxopropyl]-2,4-ImidazolidinedioneCAS#1381179-03-8.
 2. A compound of pharmaceutically acceptable saltthereof according to claim 1, wherein R¹ is H, C₁₋₄ alkyl substitutedwith one C₁₋₄ alkoxy, or C₃₋₇ monocyclic cycloalkyl.
 3. A compound ofpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound is according to Formula IIIa, IIIb, IIIc, or IIId:


4. A compound of pharmaceutically acceptable salt thereof according toclaim 1, wherein R² is H, or C₁₋₄ alkyl.
 5. A compound ofpharmaceutically acceptable salt thereof according to claim 1, whereinR^(3a) is H.
 6. A compound of pharmaceutically acceptable salt thereofaccording to claim 1, wherein R^(3b) is C₁₋₄ alkyl.
 7. A compound ofpharmaceutically acceptable salt thereof according to claim 1, whereinCy is phenyl.
 8. A compound of pharmaceutically acceptable salt thereofaccording to claim 1, wherein the subscript n is
 0. 9. A compound ofpharmaceutically acceptable salt thereof according to claim 1, whereinthe subscript n is 1 or
 2. 10. A compound of pharmaceutically acceptablesalt thereof according to claim 9, wherein R⁶ is halo, —CN, —NO₂, C₁₋₄alkyl optionally substituted with one or more halo, or C₁₋₄ alkoxyoptionally substituted with one or more halo.
 11. A compound ofpharmaceutically acceptable salt thereof according to claim 9, whereinR⁶ is F, Cl, —CH₃, or —OCH₃.
 12. A compound or pharmaceuticallyacceptable salt thereof according to claim 1, wherein the compound is:(S)-5-[(3-oxo-3-((4S)-phenylpiperidin-1-yl)propyl])imidazolidine-2,4-dione,5-[3-oxo-3-(4-phenyl-1-piperidyl)propyl]imidazolidine-2,4-dione,5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)-5-phenylimidazolidine-2,4-dione,5-methyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-isopropyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-(3-(4-(2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-cyclopropyl-5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-methyl-5-(3-oxo-3-(4-p-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-(3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(2-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-methyl-5-(3-oxo-3-(4-m-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-(3-oxo-3-(4-phenylpiperidin-1-yl)propyl)-5-(pyridin-3-yl)imidazolidine-2,4-dione,5-cyclopropyl-5-(3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(3-chlorophenyl)piperidin-1-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione,5-cyclopropyl-5-(3-(4-(3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-cyclopropyl-52-methyl-3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-methyl-5-((S)-2-methyl-3-oxo-3-(4-phenylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-(3-(4-(4-chlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3,5-dichlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-fluorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-methyl-5-(2-methyl-3-oxo-3-(4-m-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,5-(3-(4-(3-fluorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3-chlorophenyl)piperidin-1-yl)-2-methyl-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-5-methoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(2,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-chloro-5-methoxy-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(2,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(3,4-difluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3,4-difluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(3,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(4-fluoro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(3,4-difluorophenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-fluoro-3-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3,4-difluorophenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-methyl-5-(3-oxo-3-(4-o-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,(R)-5-(3-oxo-3-(4-o-tolylpiperidin-1-yl)propyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(4-chloro-5-fluoro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4-chloro-5-fluoro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3-chloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3-chloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(3,4-dichloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3,4-dichloro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(R)-5-(3-(4-(3,5-dichloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(4,5-dichloro-2-methylphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(4-fluoro-3,5-dimethoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-(3-(4-(3-chloro-4-fluoro-5-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,(R)-5-(3-(4-(3-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,5-(3-(4-(3-chloro-2-methoxyphenyl)piperidin-1-yl)-3-oxopropyl)-5-methylimidazolidine-2,4-dione,5-cyclopropyl-5-(3-((3R,4R)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(S)-5-cyclopropyl-5-(3-((3R,4S)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(S)-5-cyclopropyl-5-(3-((3R,4R)-4-(3,4-difluorophenyl)-3-methylpiperidin-1-yl)-3-oxopropyl)imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(3-chloro-4-fluoro-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-fluoro-3,5-dimethoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-fluoro-3,5-dimethoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-fluoro-5-methoxy-2-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(3-chloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-ethoxy-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-ethoxy-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-2-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-[4-chloro-3-(dimethylamino)-5-methoxy-phenyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-[4-chloro-3-(dimethylamino)-5-methoxy-phenyl]-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,5-[3-[4-(4,5-dichloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-(6-methyl-2-pyridyl)imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3,5-dimethyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-[4-chloro-3-(trifluoromethyl)phenyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4,5-dichloro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[(3R,4R)-4-(3,4-difluorophenyl)-3-methyl-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-ethyl-5-methoxy-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,5-[3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,5-[3-[4-(4-chloro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,5-[3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,5-[3-[4-(4-chloro-5-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-(5-chloro-4-fluoro-2-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-[5-(2-fluorophenyl)-2-thienyl]-1-piperidyl]-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione,(5R)-5-[3-[4-(4-chloro-3-methoxy-5-methyl-phenyl)-1-piperidyl]-3-oxo-propyl]imidazolidine-2,4-dione,5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,or5-[3-[4-(4-chloro-3-fluoro-5-methoxy-phenyl)-1-piperidyl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione.13. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof according to claim 1, and apharmaceutically acceptable carrier.
 14. A method for treatment ofinflammatory diseases, and/or diseases involving degradation ofcartilage and/or disruption of cartilage homeostasis in a humancomprising administering an effective amount of the compound or apharmaceutically acceptable salt thereof of claim 1, to said human. 15.A method for treatment of inflammatory diseases, and/or diseasesinvolving degradation of cartilage and/or disruption of cartilagehomeostasis in a human comprising administering an effective amount ofthe pharmaceutical composition according to claim 13 to the human.